Speckle-type POZ protein (SPOP) is a substrate-binding adaptor of the CULLIN3/RING-box1 E3 ubiquitin ligase complex. SPOP is frequently mutated in prostate and endometrial cancers, whereas it is overexpressed in renal cell carcinoma (RCC). SPOP can mediate both degradable and nondegradable polyubiquitination of a number of substrates with diverse biological functions such as androgen receptor (AR), SRC-3, TRIM24, BRD4, PD-L1, 53BP1, GLP/G9a, c-Myc, SENP7, among others. Cancer-associated SPOP mutants often impair SPOP binding and polyubiquitination of its substrates to influence various cancer-relevant pathways, which include androgen/AR signaling, DNA repair and methylation, cellular stress surveillance, cancer metabolism, and immunity. Although SPOP is recognized as a tumor suppressor in prostate and endometrial cancers, it acts like an oncoprotein in RCC. This review provides an overview of the recent progress in understanding of the upstream regulators of SPOP and its downstream targets, highlights the significant impact of SPOP mutations and overexpression on cancer pathogenesis, and discusses the potential of targeting SPOP for cancer treatment.

Ubiquitination is a common post-translational modification (PTM) that triggers protein degradation or signaling transduction, and abnormal protein ubiquitination could lead to diseases such as cancer (1). There are three enzymes involved in the process of ubiquitination, including E1 (ubiquitin activation enzyme), E2 (ubiquitin conjugation enzyme), and E3 (ubiquitin ligase protein or complex), which binds to substrates and facilitates E2-mediated conjugation of the small ubiquitin protein to the substrates. Speckle-type POZ protein (SPOP) is a substrate-binding adaptor of the CULLIN3 (CUL3)/RING-box1 (RBX1) E3 ubiquitin ligase complex.

SPOP is the mammalian homolog of Drosophila hedgehog (Hh)-induced BTB protein (Hib) and participates in development of Drosophila (2). Studies with vertebrate animal models show that SPOP gene deletion causes disorders in development, confirming the importance of SPOP in normal physiology and development (3–5). Notably, both human and plant SPOP proteins can form dimers or oligomers (6), highlighting that the function of SPOP is evolutionarily conserved.

Because SPOP-related research is a highly dynamic area of studies, we attempt to provide a systematic, up-to-date overview about regulation and functions of SPOP, deregulations of SPOP in disease states such as cancer, and how to target deregulated SPOP for cancer therapies. Abbreviations used in this review are listed in Supplementary Table S1 and the major substrates of SPOP identified thus far are listed in Supplementary Table S2.

SPOP contains the N-terminal MATH domain, internal BTB and BACK domains, and C-terminal nuclear localization signal (NLS; ref. 7). The evolutionarily conserved MATH domain is responsible for substrate binding (Fig. 1A and B; ref. 7). The vast majority of cancer-associated SPOP mutations are detected in this region (8). Almost all substrates of SPOP contain one or more typical or atypical SPOP-binding consensus (SBC; φ-π-S-S/T-S/T; φ-nonpolar, π-polar amino acid) motifs that are bound by the MATH domain (Fig. 1A and C). Although the affinity of a single SBC motif for the MATH domain could be weak, oligomerization mediated through the BTB and BACK domains allows simultaneous binding of SPOP with multiple SBC motifs of the substrate (9), thereby promoting efficient polyubiquitination of the target (Fig. 1D; ref. 10). SPOP oligomerization is also important for the formation of the SPOP/substrate condensates due to liquid–liquid phase separation (LLPS) and its localization in such membraneless organelle (11–13), which enables SPOP to target substrates at a maximum level of ubiquitination (Supplementary Fig. S1A; ref. 9). Cancer-associated SPOP mutations in BTB and BACK domains may disrupt the oligomerization and LLPS of SPOP and inhibit the functions of wild-type SPOP by exerting a dominant-negative effect (13, 14). Notably, a fair number of SPOP substrates such as HIPK2 and 53BP1 do not undergo protein degradation upon polyubiquitination (Supplementary Table S2), which is a key feature of the CUL3-based E3 ligase (15) although the underlying mechanisms are poorly understood.

Figure 1.

The domain structure of SPOP protein and SBC motifs in SPOP substrates. A, SPOP protein is a substrate-binding adaptor in the CULLIN3/RING-box1 E3 ubiquitin ligase complex. The MATH domain of SPOP recruits substrates by recognizing the SBC motif(s). The BTB domain is responsible for the dimerization and the CUL3 binding of SPOP. The BACK domain mediates oligomerization of SPOP. The NLS sequence mediates nuclear localization of SPOP. B, Comparison of amino acid sequences of the MATH domain (28–166 in human) of SPOP protein from various species (data from UniProt; https://www.uniprot.org/). C, Examples of SPOP substrates with one SBC motif (typical or atypical) or multiple SBC motifs in each target protein. D, BTB and BACK domains are responsible for dimerization and oligomerization of SPOP. (Created with BioRender.com.)

Figure 1.

The domain structure of SPOP protein and SBC motifs in SPOP substrates. A, SPOP protein is a substrate-binding adaptor in the CULLIN3/RING-box1 E3 ubiquitin ligase complex. The MATH domain of SPOP recruits substrates by recognizing the SBC motif(s). The BTB domain is responsible for the dimerization and the CUL3 binding of SPOP. The BACK domain mediates oligomerization of SPOP. The NLS sequence mediates nuclear localization of SPOP. B, Comparison of amino acid sequences of the MATH domain (28–166 in human) of SPOP protein from various species (data from UniProt; https://www.uniprot.org/). C, Examples of SPOP substrates with one SBC motif (typical or atypical) or multiple SBC motifs in each target protein. D, BTB and BACK domains are responsible for dimerization and oligomerization of SPOP. (Created with BioRender.com.)

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The BTB domain mediates SPOP binding with CUL3 and is important for the E3 ubiquitin ligase enzymatic activity of this complex (7). More than 70% of SPOP proteins are localized in the nucleus and this is consistent with the observation that SPOP contains an NLS, but no nuclear export signal (NES; refs. 7, 16), highlighting the importance of NLS in controlling the cellular distribution of SPOP protein. The regulation and function of NLS could be extremely important in renal cell carcinoma (RCC) because even in the absence of a NES-overexpressed SPOP, proteins are primarily localized in the cytoplasm of RCC cells (17, 18).

Previous studies have shown that expression and function of SPOP can be regulated at the transcriptional and translational levels (Supplementary Table S3) and by PTMs such as phosphorylation, ubiquitination, SUMOylation, acetylation, and protein–protein interaction (Supplementary Table S4).

Phosphorylation and ubiquitination

Protein phosphorylation widely affects the interaction between adaptors/receptors with substrates and subsequent ubiquitination of target proteins (19). LIMK2 and AURKA kinases decrease the stability of SPOP via phosphorylation of SPOP at different residues. Notably, both of them have been identified as degradable substrates of SPOP, suggesting a negative feedback regulation (20, 21). By contrast, CDK4/6 induces the stabilization of SPOP protein via phosphorylation at Ser6 (22). In addition, ATR inhibitor suppresses ATR–CHK1 signaling and subsequently induces the activation of CDK1, promoting SPOP phosphorylation and stabilization (23). SPOP can be phosphorylated by ATM at Ser 119 in response to DNA damage and the functional consequences are very complex (24–26) and discussed below in detail. Considering the complexity of regulation and functional consequences of SPOP phosphorylation, targeting phosphorylation of specific residues rather than simply inhibiting or activating phosphorylation may be beneficial.

Although the SPOP phosphorylation sites identified so far are located in the MATH domain (Supplementary Fig. S1B), a recent study shows that GRK2 phosphorylates SPOP at Ser222 in the BTB domain, which inhibits SPOP dimerization and enhances auto-ubiquitination under glutamine deprivation condition (27), hinting that the functional impact of phosphorylation of other serine and threonine residues in BTB and BACK domains warrants further investigation. Inhibition of Cyclin D–CDK4-mediated phosphorylation of SPOP by CDK4/6 inhibitor induces SPOP ubiquitination and degradation mediated by the anaphase-promoting complex/cyclosome (APC/C) activator CDH1 (22). Snail interacts with the BTB domain of SPOP and facilitates SPOP ubiquitination and degradation in a CUL3-dependent manner (28).

SUMOylation and acetylation

SUMOylation, a ubiquitination-like form of PTM also occurs on the lysine residue of target protein. This modification alters the function and cellular localization of SPOP, such as the formation of speckle-like structure in the nucleus mediated by LLPS (Supplementary Fig. S1A; refs. 29, 30). A previous study identifies more than 6,000 SUMOylated proteins, including SPOP, in which eight putative SUMOylation residues are found (Supplementary Fig. S1C; Supplementary Table S4; ref. 31). Lys110 is a possible SUMOylation in 109AKGE112 that perfectly matches with the consensus SUMO-interacting motif, Ψ-K-x-E/D, where Ψ is a hydrophobic amino acid (I, V, L, A, P, or M), K is lysine, x is an arbitrary amino acid, and E/D is glutamic or aspartic acid. Notably, Lys129 is another possible SUMOylation site that is also a hotpot mutation residue in prostate cancer (31). However, there are only a handful of studies focusing on the impact of SUMOylation on SPOP functions. Moreover, SPOP is predicted to be acetylated at Lys339, which happens to be a SUMOylation site in the BACK domain (31). SPOP acetylation is thought to promote its aggregation with substrates (Supplementary Fig. S1A and S1C). The acetylation and SUMOylation of SPOP are likely involved in LLPS of SPOP and substrates (7, 11, 12, 32).

Protein–protein interaction

SPOP-like

The SPOP-like (SPOPL) protein shares approximately 85% sequence homology with SPOP. SPOPL can form a homodimer and a hetero-dimer or -tetramer with SPOP (Supplementary Fig. S2A, left); however, different from SPOP, SPOPL cannot form an oligomer because of an insert in its BACK domain (33). It is conceivable that SPOP and SPOPL might be functionally complementary to each other, although SPOPL does not seemingly work as efficiently or broadly as SPOP due to the incompetence to form an oligomer. Functioning through a distinct mechanism of action, cancer-associated SPOP mutations, which mainly occur in the substrate-binding MATH domain, allows mutated SPOP to form a dimer or oligomer with wild-type SPOP, thereby executing a dominant negative effect. Notably, SPOPL-deleted prostate cancers are exceptionally sensitive to antiandrogen therapy in a manner similar to SPOP-mutated prostate cancers (34). Thus, SPOPL deletion and SPOP mutation might affect similar signaling pathways in prostate cancer, although the precise mechanism remains to be investigated.

The partnership between SPOP and SPOPL may create a molecular rheostat that can fine-tune the ubiquitination activity of SPOP (Supplementary Fig. S2A, right; ref. 32). Structurally, SPOPL may function as a flexible switch that regulates the function of SPOP when excessive ubiquitination activity is not required; however, the ubiquitination activity of SPOP can be augmented when needed such as in response to excessive amounts of substrates or cellular stress (24, 25, 35).

G3BP1 as a “pseudosubstrate” of SPOP

A recent study shows that G3BP1, a key component of stress granule (SG) competes with substrates to bind the MATH domain of SPOP but cannot be degraded by the SPOP–CUL3 E3 ligase, thereby blocking SPOP-mediated polyubiquitination of its substrates such as androgen receptor (AR) and SRC-3 (Supplementary Fig. S2B; ref. 35). Notably, only nuclear localized G3BP1 can function as a “pseudosubstrate” to interact with SPOP (35). Future studies on the structural differences between “real substrates” and “pseudosubstrates” of SPOP are expected to enhance the understanding of the structural basis of regulation of SPOP by upstream and downstream signaling pathways or molecules (7). A number of small-molecule inhibitors of SPOP such as compound 6b have been identified (36). The small-molecule compound 6b may inhibit the ubiquitination activity of SPOP as a “pseudosubstrate,” suggesting that the “pseudosubstrate” mechanism could be harnessed to therapeutically target overexpressed SPOP in cancers such as RCC.

SPOP proteins function as a tumor suppressor in certain types of cancers such as prostate cancer and endometrial cancer by primarily localizing in the nucleus, although a small portion of this protein can also be detected in the cytoplasm (Fig. 2; refs. 37–39). SPOP gene is frequently mutated in prostate cancer (6%–15%) and endometrial cancer (5.7%–10%; Supplementary Fig. S2C; Supplementary Table S5; refs. 40, 41). Notably, the majority of cancer-associated SPOP mutations are detected in the MATH domain and are hemizygous mutations (with one exception in prostate cancer; ref. 14), and they can act as dominant-negative or loss-of-function mutations by forming crippled heterogenous dimer/oligomer or homogenous dimer/oligomer, respectively (Supplementary Fig. S2D; refs. 14, 40). Besides gene mutations, it has been shown that SPOP is aberrantly overexpressed in RCC and functions as an oncoprotein localized primarily in the cytoplasm (Fig. 2; refs. 17, 39). It appears that distinct strategies are necessary for targeting of SPOP mutations and overexpression for cancer therapy.

Figure 2.

SPOP functions as a tumor suppressor and oncoprotein. Most SPOP proteins are located primarily in the nucleus to form speckles. SPOP functions as a tumor suppressor by promoting ubiquitination and degradation or functional regulation of oncogenic proteins such as AR and BRD4 in both nucleus and cytoplasm. Under certain cellular stress conditions such as hypoxia in RCC, however, overexpressed SPOP proteins accumulate in the cytoplasm to promote degradation of a handful of tumor-suppressor proteins such as PTEN and LATS1. This process has been suspected to be mediated through the PTMs of SPOP. (Created with BioRender.com.)

Figure 2.

SPOP functions as a tumor suppressor and oncoprotein. Most SPOP proteins are located primarily in the nucleus to form speckles. SPOP functions as a tumor suppressor by promoting ubiquitination and degradation or functional regulation of oncogenic proteins such as AR and BRD4 in both nucleus and cytoplasm. Under certain cellular stress conditions such as hypoxia in RCC, however, overexpressed SPOP proteins accumulate in the cytoplasm to promote degradation of a handful of tumor-suppressor proteins such as PTEN and LATS1. This process has been suspected to be mediated through the PTMs of SPOP. (Created with BioRender.com.)

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SPOP mutations in prostate cancer

SPOP-mutated prostate tumors represent a unique subset of primary and advanced prostate cancer with several special features, including mutual exclusivity with TMPRSS2-ERG gene fusion, high AR activity, and DNA hypermethylation (40, 42, 43).

Hyperactivation of AR signaling in SPOP-mutated prostate cancer

Most newly diagnosed prostate cancers are androgen-responsible and androgen-deprivation therapy (ADT) is the mainstay treatment of this disease (44). AR has been identified as a degradable substrate of SPOP (45, 46), revealing a direct connection to hyperactivation of the AR signaling observed in SPOP-mutated prostate cancers in patients (42). Accordingly, expression of SPOP F102C mutant increases prostate cancer xenograft growth in mice (46). SPOP also inhibits AR signaling by modulating a number of AR transcription co-regulators such as SRC-3, TRIM24, BRD4, p300, and Gli3 (47–52), thereby providing a plausible explanation for the high AR activities in SPOP-mutated prostate cancer in comparison with other molecular subtypes (Fig. 2; ref. 42).

Increasing evidence indicates that SPOP-mutated prostate cancers are hypersensitive to AR pathway inhibitors (ARPI). Prostate cancer patients with SPOP mutations, including hotpot mutations (Y87C/N/S, F125C/L, W131C, and F133C/L/V/S) and six other mutations (E50K, S105F, Q120R, R121P, G148E, and A187T) and SPOP F133V murine prostate organoids are hypersensitive to ADT or ARPIs such as abiraterone (34, 51, 53, 54). In addition, patients with high-risk localized prostate cancer–harboring SPOP mutations and/or SPOPL gene deletion are exceptionally responsive to ARPIs such as enzalutamide (34), highlighting the effectiveness of AR inhibition for treatment SPOP-mutated prostate cancer. Paradoxically, clinical studies with different patient cohorts reveal that approximately 50% of SPOP mutated metastatic castration-resistant prostate cancers remain refractory to ARPIs (54, 55), highlighting the urgent need to investigate the resistance mechanisms.

Genomic instability in SPOP-mutated prostate cancer

SPOP plays crucial roles in DNA damage repair and DNA replication to safeguard genomic stability (Fig. 2). Previous studies on SPOP regulation of genomic stability have been reviewed before (56, 57), but more advances in this area have been made very recently (25, 58).

SPOP can be phosphorylated at Ser119 by activated ATM in response to DNA damage (24, 25). Specifically, Ser119 phosphorylation increases the capacity of SPOP to mediate the nondegradable ubiquitination of HIPK2 and 53BP1 and degradable ubiquitination of cell division–related proteins, promoting DNA repair via errorless homologous recombination over error-prone nonhomologous end joining (3, 24–26). Given that the types of ubiquitin chains attached to the substrates are dependent on the usage of E2 ubiquitin-conjugating enzymes, it would be intriguing to determine whether SPOP-mediated nondegradable ubiquitination of HIPK2 and 53BP1 is due to the recruitment of different E2s after ATM-mediated phosphorylation of SPOP. By contrast, ubiquitination of MCM3 and DNA duplex unwinding proteins are inhibited to prevent cell-cycle progression (26).

SPOP S119A/N mutants diminish SPOP affinity toward substrates induced by ATM-mediated phosphorylation of SPOP, thereby affecting the sensibility of SPOP-mutated cells to DNA damage–based therapies such as radiotherapy or platinum alone or together (40). SPOP also mediates nondegradable polyubiquitination of Geminin, a key negative regulator of DNA replication origin firing licensing during S phase, therefore preventing the risk of excessive DNA replication (58). Although F133V, one of the most frequent mutation of SPOP in prostate cancer, often acts as a dominant-negative mutant in various biological processes (14, 40), a previous study suggests that this mutant also exhibits a gain-of-function in controlling the level of endo/exonuclease MRE11 and the DNA–protein cross-link repair process in AR-positive prostate cancer cells (59).

DNA hypermethylation in SPOP-mutated prostate cancer

The Cancer Genome Atlas (TCGA) data show that DNA hypermethylation is one of the major features of SPOP-mutated prostate cancer (42). It has been uncovered that SPOP inhibits DNA methylation by inducing polyubiquitination and degradation of histone methyltransferase GLP, a key factor that can facilitate the recruitment of DNA methyltransferases DNMTs onto chromatin (Fig. 2). However, prostate cancer–associated SPOP mutations (Y87C, F102C, F133V, and Q165P) cause stabilization of GLP and enhance DNMT recruitment, thereby promoting DNA hypermethylation and transcriptional silencing of a large number of tumor-suppressor genes (60). Accordingly, both SPOP Q165P patient-derived xenograft (PDX) tumors and SPOP F102C–expressing prostate cancer xenografts are hypersensitive to DNA methylation inhibitor 5-AzaC alone or in combination with chemotherapeutic drugs like docetaxel, highlighting a viable therapeutic option for the treatment of SPOP-mutated prostate cancer (60).

Mitochondrial dysfunction in SPOP-mutated prostate cancer

SPOP-mutated prostate cancer cells show hyperactive mitochondrial division (61). SPOP mediates nondegradable ubiquitination and disconnection of INF2 from the endoplasmic reticulum and reduces its interaction with DRP1, a protein essential for mitochondrial division, thereby inhibiting mitochondrial division (Fig. 2; refs. 61, 62). However, prostate cancer–associated SPOP hotpot mutants (Y87N, F125V, and F133L) fail to ubiquitinate INF2, causing mitochondria dysfunction and ultimately facilitating prostate cancer progression (61). Mitochondrial division inhibitors may be applicable for treatment of SPOP-mutated prostate cancer.

Disordered immune microenvironment in SPOP-mutated prostate cancer

Immune checkpoint blockade (ICB) therapy, which inhibits the activity of the immune checkpoint molecules PD-1 and its ligands PD-L1/2, has been approved for cancer treatment (63). SPOP has been shown to suppress the immune evasion of cancer cells via degrading PD-L1 whereas prostate cancer–associated SPOP mutants such as F102C induce accumulation of PD-L1 protein and immune escape in prostate cancer xenografts in mice (22). Notably, either too high or too low PD-L1 protein levels are not helpful for ICB therapy. For example, inhibition of CDK4/6 elevates PD-L1 protein levels, largely by inhibiting Cyclin D-CDK4-mediated phosphorylation and degradation of SPOP mediated by activated APC/CCDH1 E3 ligase (22). However, the combined treatment of CDK4/6 inhibitor and anti–PD-1/PD-L1 immunotherapy exhibits enhanced tumor regression and dramatically improves overall survival (OS) rates in xenograft models, suggesting that appropriate protein levels of PD-1 and PD-L1 are required for anti–PD-1/PD-L1 immunotherapy, which may be applicable to patients with prostate cancer with SPOP-WT and low PD-L1 protein level (22). In addition, ATR inhibitors appear to be effective when combined with anti–PD-1/PD-L1 immunotherapy and this appears to be mediated through ATR inhibition–induced activation of CDK1 (a known negative regulator of CDH1), SPOP stabilization, and reduced expression of PD-L1 protein due to enhanced degradation (23).

It is highly feasible to enhance the efficacy of ICB therapy by interfering with the SPOP–PD-L1 axis. In esophageal cancer, c-Myb mediates immune escape via the miR-145–5p–SPOP–PD-L1 axis (64). In addition, phosphorylation of PD-L1 at Thr285 and Thr290 by CK2 disrupts PD-L1 binding with SPOP, protecting PD-L1 from destruction by the ubiquitin proteasome system (UPS; ref. 65). A recent study shows that exosomal microRNA-17–5p derived from tumor stem cells inhibits anticancer immunity via decreasing SPOP expression but increasing PD-L1 level in colorectal cancer, thus linking the exosome activity to SPOP regulation of cancer (66). SPOP also regulates the immune microenvironment through several other pathways, including SPOP-mediated negative regulation of MyD88 and RAS/MAPK signaling pathways (Fig. 2; refs. 67–69).

Abnormal cellular stress response in SPOP-mutated prostate cancer

SGs allow cells to tolerate cellular stress and survive whereas excessive SG formation favors the occurrence, progression, and drug resistance of cancer (70). SPOP suppresses SG assembly by promoting the polyubiquitination and degradation of Caprin1, an SG-nucleating oncoprotein. Prostate cancer–associated SPOP mutants, especially Y87N, F125V, and F133L, lead to the elevation of the Caprin1 protein level, thus enhancing cancer cell survival and resistance to docetaxel (Fig. 2; ref. 71). SPOP has also been shown to promote non-degradable polyubiquitination and inhibit phase condensation and dimerization of p62, and therefore cancer cells lose the ability to effectively cope with oxidative stress due to Keap1 activation–mediated degradation of Nrf2 (Fig. 2; ref. 72). In addition, SPOP inhibits p62-mediated autophagy, suggesting that SPOP is involved in modulating multiple p62-associated signaling pathways; however, prostate cancer–associated SPOP mutants, especially Y87N, F125V, and F133L, activate the p62-related oncogenic signaling pathway (72).

Dysregulated cancer metabolism in SPOP-mutated prostate cancer and other cancers

The aberrant metabolism of cancers mediates aggressive cancer phenotypes such as drug resistance and is a potential cancer therapeutic target (73). Increasing evidence indicates that SPOP is related to the deregulation of cancer metabolism, including glucose metabolism, lipid metabolism, androgenesis, and amino acid metabolism (Fig. 2; ref. 74).

Glucose metabolism.

Aerobic glycolysis, also known as the Warburg effect, is the most distinguishing change of metabolism between normal and cancer cells, which can be induced by the activation of c-Myc oncoprotein (Fig. 2; ref. 75). SPOP has been shown to inhibit cancer growth by inducing ubiquitination and degradation of c-Myc (76); however, the circular RNA CircECE1 interacts with c-Myc to prevent SPOP-mediated ubiquitination of c-Myc and inhibition of the Warburg effect (77). In addition, SPOP is also known as Pdx1 C-terminal–interacting factor 1 (PCIF1) and it inhibits the transcriptional activities of Pdx1, a factor required for the survival of islet β cells via regulation of glucose homeostasis (78, 79).

Lipid metabolism.

Cholesterol is the raw material for the synthesis of various hormones, especially androgen synthesis in prostate cancer cells (80). SPOP mediates the polyubiquitination and proteasomal degradation of FASN to regulate cholesterol biosynthesis (81). BET proteins have been identified by multiple groups as degradable substrates of SPOP (49, 50, 82). However, prostate cancer–associated SPOP mutants such as F133V induce the accumulation of BET proteins, resulting in transcriptional activation of cholesterol biosynthesis–related genes, such as FDFT1, DHCR24, DHCR7, and MVD (49). In addition to regulating cholesterol biosynthesis pathways, SPOP also promotes stabilization of 17βHSD4, an enzyme antagonizing androgen synthesis by causing nondegradable polyubiquitination, which competes with SKP2-mediated polyubiquitination and proteasomal degradation of 17βHSD4 (Fig. 2; ref. 83). However, prostate cancer–associated SPOP mutants F102C and F133 L augment testosterone synthesis and aberrant activation of AR signaling in prostate cancer cells. Similarly, SPOP Q165P prostate cancer PDX tumors also display a superior growth rate with increased intratumoral androgen synthesis (83). Given that other sex hormones are also derived from lipids, SPOP may also play a role in other hormone-driven cancers such as endometrial and breast cancers by regulating lipid metabolism (84).

Amino acid metabolism.

An increase in serine synthesis has been found in many cancers such as colorectal and breast cancers (85). SPOP inhibits serine synthesis via the ubiquitination degradation of ILF3 in colorectal cancer (86). Similar to prostate cancer, colorectal cancer–associated SPOP mutations (R70Q, R138C, and L142I) occur in the MATH domain and fail to mediate ILF3 polyubiquitination and degradation (86). Cancer cells are also addicted to glutamine to accelerate their growth, which often leads to severe glutamine shortage in the cancer microenvironment (87). Notably, SPOP has been shown to inhibit breast cancer cell glutamine uptake by mediating ASCT2 polyubiquitination and degradation (27). Interestingly, glutamine deprivation triggers SPOP auto-ubiquitination and degradation via GRK2-mediated SPOP phosphorylation (27). Although the neddylation inhibitor MLN4924 has the potential as an anticancer drug, it fails in clinical trials for certain cancer types and this may be due to increased glutamine uptake-mediated inactivation of the SPOP tumor suppressor and accumulation of ASCT2 (Fig. 2; refs. 27, 87). These findings suggest the feasibility of ASCT2 inhibitor V-9302 in combination with MLN4924 for treatment of cancers (88).

SPOP regulation of cellular senescence in prostate cancer

Cellular senescence triggered by oncogenic activation is an important tumor suppression mechanism (89, 90). SPOP is upregulated during senescence and SPOP knockdown significantly suppresses cellular senescence (91). SPOP promotes cell senescence via ubiquitination and degradation of the SENP7 deSUMOylase, increasing HP1α sumoylation to form the senescence-associated heterochromatin foci and leading to the cell proliferation–associated epigenetic gene silencing; however, these effects were abolished by prostate cancer–associated SPOP mutants (Y87C and F102C; Fig. 2; ref. 91). The study predicts the low sensitivity of SPOP-mutated prostate cancer to the treatment of cancer with cellular senescence-inducing agents, but supports treatment by suppressing SENP7 in SPOP-mutated prostate cancer.

SPOP mutations in endometrial cancer and uterine carcinosarcoma

Estrogen receptor alpha (ERα) has been identified as a degradable substrate of SPOP, linking SPOP to regulation of the female reproductive system (92, 93). Similar to the scenario in prostate cancer, most endometrial cancer–associated SPOP mutants are located in the MATH domain (Supplementary Fig. S2C), suggesting that similar cancer regulatory roles of SPOP may occur in endometrial cancer. Endometrial cancer–associated SPOP mutants (E47K, E50K, G75R, S80R, and D140G) are unable to promote ERα polyubiquitination and degradation (92). SPOP can also induce the polyubiquitination and degradation of ZBTB3 to inhibit Shh signaling, whereas endometrial cancer–associated SPOP mutants, especially G75R, P94A, and M117I, lead to Shh upregulation in endometrial cancer cells, supporting the notion that RUSKI-43, a small-molecule inhibitor of Shh could be a promising choice for the treatment of SPOP-mutated endometrial cancer (94).

Unlike the situation in prostate cancer that SPOP mutations cause BRD4 protein stabilization and BET inhibitor resistance (49, 50), endometrial cancer–associated SPOP mutants, especially E50K and R121Q, preferentially degrade BRD4 and increase BET inhibitor sensitivity in endometrial cancer cells, suggesting that SPOP E50K and R121Q are gain-of-function mutants (82). In agreement with these observations, the SPOP mutant spectrum in endometrial cancer does not overlap with that in prostate cancer except the W131 residue (Supplementary Fig. S2C), implying that distinct mechanisms of action may associate with SPOP mutations occurred in prostate cancer and endometrial cancer (92). Even though the mutants of different residues are located in the same domain, they may cause different conformational changes in SPOP proteins, thereby resulting in completely opposite functional consequences (82). With the advances in cryogenic electron microscopy (cryo-EM) technology, it is conceivable that future studies on the structural bases of these biological and biochemical differences between prostate cancer- and endometrial cancer–associated SPOP mutants could lead to the new breakthrough in understanding the structure biology and working mechanism of SPOP mutants in cancers. Considering the key roles of SPOP in the reproductive system, gender difference may be an important factor influencing the outputs of SPOP function due to distinct hormonal backgrounds (androgens vs. estrogens) of these cancer types.

Consistent with endometrial and prostate cancers, uterine carcinosarcoma–associated SPOP mutants (Supplementary Table S5) are also primarily located in the MATH domain but in different residues, indicating distinct mechanisms of action. Whether the difference contributes to the distinct biological characteristics between uterine carcinosarcoma and endometrial cancer remains unclear.

SPOP deregulation in breast cancer

SPOP mutations in breast cancer have not been fully identified, but SPOP deregulation has been reported in breast cancer. SPOP promotes the polyubiquitination and degradation of c-Myc in triple-negative breast cancer, whereas this process can be prevented by c-Myc interaction with lncRNA LINC01638 (76, 95). In addition, SPOP induces the polyubiquitination and degradation of SRC-3 in a phosphorylation-dependent manner in breast cancer cells (96). Similar to AR and ERα, progesterone receptors (PR) nuclear transcriptional factors have been identified as degradable substrates of SPOP, and SPOP suppresses progesterone-mediated PR transactivation and inhibits S-phase entry and ERK1/2 activation (97). SPOP also inhibits breast cancer growth by degrading ERα, and this effect is enhanced by GPER1 although the underlying mechanism remains unclear (98). Notably, although SPOP inhibits the growth of breast cancer by limiting glutamine uptake in breast cancer cells (27), SPOP can also promote breast cancer cell distant metastases by degrading BRMS1 (99), suggesting multifacet roles of SPOP in breast cancer.

The observations that three sex hormone receptors, including AR, ERα, and PRs are the substrates of SPOP, suggest that SPOP is functionally important in the reproductive system. In addition, X chromosome inactivation in female cells is thought to be related to SPOP-mediated monoubiquitination/polyubiquitination and deposition of macroH2A1 and BMI1, a key component of Polycomb-repressive complex 1 (PRC1; refs. 100, 101). Furthermore, SPOP mediates polyubiquitination and degradation of DPPA2 to inhibit the growth of testicular germ cell tumors (102). It is important to study the functional differences of SPOP in different gender backgrounds.

SPOP overexpression in RCC

In contrast with the tumor-suppressive role of SPOP in many cancers such as prostate and endometrial cancers, the oncogenic role of SPOP in RCC has been reported (Fig. 2; refs. 17, 37–39). SPOP is overexpressed but not mutated in RCC tissues at mRNA and protein levels and SPOP protein is abnormally accumulated primarily in the cytoplasm of RCC cells (Fig. 2; refs. 17, 18, 103). It has been shown that increased expression of SPOP in RCC is mediated, at least in part, by enhanced transcription of SPOP mRNA mediated by hyperactivated HIFs under hypoxia (103). Hypoxia may also play a role in the localization of SPOP in the cytoplasm, although the exact underlying mechanisms are largely unclear. Domain structure analysis indicates that there is no NES present in SPOP protein and it is possible that hypoxia-induced PTMs may play an essential role in causing the shuttling of SPOP protein from the nucleus to cytoplasm (Fig. 2). Given that the binding of cargo proteins to substrates is affected by PTM such as phosphorylation, ubiquitination, and SUMOylation (104), it can be speculated that the affinity between SPOP and cargo proteins may be influenced by hypoxic stress in RCC.

Previous studies report that the oncogenic functions of SPOP are largely due to the abnormal degradation of tumor suppressor proteins in the cytoplasm, including PTEN, DUSP7, Daxx, Gli2, and LATS1 (17). It has been suggested that a high concentration of SPOP in the cytoplasm may trigger LLPS, thereby increasing SPOP binding and degradation of a handful of tumor-suppressor proteins (11). Indeed, a previous study reports that SPOP inhibitor compound 6b inhibits RCC by disturbing LLPS (36). Therefore, the disruption of LLPS may be a viable treatment for RCC with SPOP proteins accumulated in the cytoplasm.

It is possible that primary localization of SPOP in the cytoplasm may result in impaired degradation of SPOP substrates present in the nucleus such as AR in RCC under hypoxic stress, mimicking the effects of SPOP mutants on its targets in the nucleus (Fig. 2). Indeed, proteolysis targeting chimeras (PROTAC) built on the basis of VHL ligand to target AR protein have been developed to accommodate the insufficient degradation of AR protein in SPOP-overexpressed RCC and SPOP-mutated prostate cancer (105). Treatment with antiandrogen enzalutamide enhances SPOP-mediated AR degradation and the anticancer effect of receptor tyrosine kinase inhibitor sunitinib in AR-positive RCC (106).

In addition to RCC and breast cancer, the oncogenic role of SPOP has also been reported in other cancer types. SPOP promotes tumor growth of paclitaxel-resistant cervical cancer cells via promoting ubiquitination and degradation of DAPK1 (107). Discoveries of the oncogenic roles of SPOP can help improve the targeting of SPOP-overexpressed cancers.

SPOP mutations in diffuse large B-cell lymphoma and other cancers

Various lymphoid malignancies, including diffuse large B-cell lymphoma (DLBCL), exhibit pathological NF-κB activation due to the disruption of key components of the NF-κB signaling pathway, such as MyD88 (108). SPOP negatively regulates of NF-κB signaling by inducing the nondegradable polyubiquitination of MyD88 in DLBCL cell lines (109). Notably, lymphoid malignancy–associated SPOP mutants (G75V, F102I/Y, M117I/R, S119R, D130H/N, and D140N) are defective in mediating MyD88 polyubiquitination, resulting in constitutive activation of the NF-κB signaling pathway (109). In addition, the low expression of SPOP mRNA predicts poor OS of patients with DLBCL, and further studies on the function of SPOP in hematological diseases can help define new therapeutic options for SPOP-mutated lymphomas (109). Notably, different groups show that SPOP-mediated ubiquitination of MyD88 also regulates the inflammatory activation in hematopoietic stem cells, host defense against infection, and toll-like receptor signaling (67, 68, 110). Other studies support the tumor-suppressor role of SPOP in other cancer types such as colorectal cancer and benign thyroid nodules in which SPOP is mutated (Supplementary Table S5; ref. 37).

Prostate cancer PDX models are known difficult to establish because of the tissue origin and the requirement of androgens (111, 112). One of the major features of SPOP-mutated prostate cancer is hyperactivation of AR signaling (42), providing a possible advance for growth and survival. LuCaP 147 is the first SPOP-mutated prostate cancer PDX that was successfully established from advanced/lethal prostate cancer (113, 114). LuCaP 147 carries mutations in SPOP (Y83C) and AR genes and displays a biphasic response to the AR inhibitor bicalutamide but resistance to docetaxel and sunitinib (114).

SPOP Q165P is the second reported SPOP-mutated prostate cancer PDX model. It was established from a liver metastasis of a patient with a prostate cancer harboring a unique Q165P homozygous SPOP mutation (14). The Q165 residue is located at the C-terminal end of the MATH domain and close to the junction between MATH and BTB domains (Fig. 1A and B; ref. 7). Intriguingly, Q165P was a heterozygous mutation in primary tumor of that patient, suggesting a possible advantage of the SPOP Q165P homozygous mutation in driving prostate cancer progression (14, 37–39).

Generation of more PDXs recapitulating other biologically and clinically important SPOP mutants such as SPOP-S119A/N is warranted because they would be very useful for studies of the functional impact of these mutants on DNA damage in preclinical models (24–26). Similarly, establishment of prostate cancer PDX models for SPOP F133V can also accelerate the understanding of how to treat SPOP-mutated prostate cancer effectively (37, 38).

Besides SPOP, a number of other substrate-binding adaptors of the CUL3-based E3 ubiquitin ligase complex have been identified (115, 116). CUL3 acts as a scaffold protein and is the functional basis of the complex (115). Mutations in adaptor proteins in cancers have received much attention because of the substrate recognition specificity of adaptor proteins, whereas CUL3 mutations have received less attention (37–39, 117–120). CUL3 mutations are largely mutually exclusive with adaptor protein mutations, and CUL3 mutations lead to phenotypes that are more severe than those of any of the adaptor proteins, which is understandable because CUL3 is the basis of the whole complex and its function is expected to be broader than each individual adaptor protein (115, 117–120). It has been shown that CUL3 mutations cause EGFR-tyrosine kinase inhibitor resistance in EGFR-mutated non–small cell lung cancer and associate with the occurrence of type 2 papillary renal cell carcinoma (PRCC2), an RCC subtype with a high-mortality rate by disrupting the formation of CUL3–KEAP1 complex and inducing abnormal activation of NRF2 (119, 120). Interestingly, although few studies have focused on the role of CUL3 mutations in prostate cancer, there are 15 cases with CUL3 M299R mutant, a residue with the highest mutation frequency in the database of the Catalogue of Somatic Mutations in Cancer and 14 of them were detected in prostate cancer, further highlighting the importance of deregulation of the SPOP-CUL3 signaling pathway in prostate cancer. It is conceivable that CUL3 M299R mutant may affect the formation of the CUL3-SPOP E3 ubiquitin ligase complex, polyubiquitination of SPOP substrates, and severeness of prostate cancer phenotype. Moreover, CUL3-mutated prostate cancer may be treated with targeted therapies similar to those used for SPOP-mutated prostate cancer if they share similar clinical features.

Among cancer types analyzed, endometrial cancers have the highest mutation rate in CUL3 gene [41/529 (7.75%) in TCGA]. However, it is unclear whether occurrence and progression of CUL3-mutated endometrial cancer are partly mediated by the deregulated CUL3–SPOP E3 ubiquitin ligase complex.

PROTAC is comprised of an E3 ubiquitin ligase ligand, a linker and a ligand for the protein of interest (POI), which allows polyubiquitination and subsequent degradation of the POI mediated by the E3 ligase and UPS (Supplementary Fig. S3A; ref. 105). Some E3 ubiquitin ligases recognize a specific degradation motif known as “degron,” which was originally used as a ligand of POI to design PROTAC. Previous studies show that one or more SBC motifs are present in the substrates of SPOP. Thus, SPOP can be used to design PROTACs to treat SPOP-overexpressed RCC (7). Indeed, an SPOP-based PROTAC was developed to target RAS family proteins (wild-type and mutated KRAS) for degradation (Supplementary Fig. S3B; ref. 121). This attempt is important given that mutated KRAS is generally considered untargetable (122).

For cancers having loss-of-function mutants of SPOP, SPOP ligand-based PROTAC appears unapplicable. In contrast, AR degradation using VHL-based PROTACs is a promising method for the treatment of SPOP-mutated prostate cancer (123). Given that SPOP-mutated cancers often retain wild-type p53, MDM2-based PROTACs are used to degrade SPOP substrates in the nucleus to target SPOP-mutated cancers (40, 124). The use of this type of PROTAC may also overwhelm the ubiquitination activity of endogenous MDM2, thereby promoting cell death by preventing MDM2-mediated degradation of p53 (Supplementary Fig. S3C; ref. 124). Similar ideas can be applied to ablate the cytoplasmic oncogenic activities of SPOP to treat RCC.

SPOP is a dynamic protein involved in so many biological processes (Fig. 2). Future studies on the PTM of SPOP may enable us to understand the unique biological characteristics of SPOP such as shuttling between different cellular compartments, LLPS, and speckle formation. Studies on how SPOP LLPS works and how this process affects the regulation of SPOP, biochemical features of SPOP mutants, and effective treatment of this unique subtype of prostate cancer are warranted.

Besides the roles of SPOP in cancers, research on SPOP functions in the nervous system can be another focus area of study (125). SPOP regulates Gli3 activity and Shh signaling in the dorsoventral patterning of the mouse spinal cord (126). Genetic alterations in SPOP have been observed in many patients with prostate cancer and Alzheimer's disease (127). In addition, neurodevelopmental disorder-associated SPOP mutations (T25A, Y83C, R121Q, G132V, R138C, and D144N) are also located in the MATH domain, suggesting the similar roles of SPOP mutations in neuropathy (128).

Although SPOP-mutated cancers respond extremely well to antiandrogen therapy, approximately 50% of them remain refractory to the treatment (34, 54). Other therapeutic options for SPOP-mutated prostate cancer are apparently needed, and adjuvant therapies such as novel targeted therapy, immunotherapy, radiotherapy, and chemotherapy should not be excluded (129). Most importantly, development of new therapeutics demands comprehensive understanding of mechanisms of action of SPOP mutations or overexpression in relevant cancer types. Further development of PDXs, PROTACs, agonists, and small-molecule inhibitors of SPOP is equally vital.

No disclosures were reported.

The authors thank all the investigators for their contributions to the understanding of biochemistry, physiology, and tumor biology of wild-type and mutated SPOP proteins. The authors apologize in advance for being unable to cite all the relevant references due to the word limits of the article. This work is partially funded by The National Natural Science Foundation of China (grant no.32270821), The Natural Science Foundation of Ningbo (grant no. 2021J065), The Fundamental Research Funds for the Provincial Universities of Zhejiang (grant no. SJLZ2022004), The K.C. Wong Magna Fund in Ningbo University (to X. Jin), and the Mayo Clinic Foundation (to H. Huang).

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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