Abstract
SPOP-mediated ubiquitination and degradation of ERG restricts prostate cancer growth and invasion.
Major finding: SPOP-mediated ubiquitination and degradation of ERG restricts prostate cancer growth and invasion.
Mechanism: ERG phosphorylation at N-terminal serine residues by CKIδ promotes SPOP binding and ubiquitination.
Impact: Cancer-related TMPRSS2–ERG fusions and SPOP mutations bypass tumor-suppressive SPOP regulation of ERG.
Translocations between the androgen-responsive TMPRSS2 gene promoter and ERG transcription factor gene frequently occur in prostate cancers and give rise to high expression of N-terminal–truncated ERG fusion proteins. Cancer-associated mutations in the gene speckle-type POZ protein (SPOP), which encodes a cullin 3–based E3 ubiquitin ligase, are mutually exclusive with TMPRSS2–ERG fusions in prostate cancer, prompting An and colleagues as well as Gan and colleagues to determine whether SPOP plays a role in ERG regulation. Both groups found that SPOP bound wild-type ERG via conserved motifs in prostate cancer cells; SPOP overexpression decreased ERG levels, whereas SPOP depletion increased ERG expression and ERG-dependent gene transcription and enhanced prostate cancer cell migration, invasion, and proliferation. The SPOP-binding motif located within the ERG N-terminus was required for SPOP binding and ubiquitination and ERG-driven cell invasion. Consistent with this finding, cancer-associated TMRPSS2–ERG fusions lacking the ERG N-terminal region were resistant to SPOP binding and regulation and highly expressed in human prostate cancer specimens. Moreover, prostate cancer–associated SPOP mutations that prevent binding to the ERG N-terminus were detected in TMPRSS2–ERG-negative prostate cancers. Gan and colleagues also showed that casein kinase I δ (CKIδ)–mediated ERG phosphorylation at the N-terminal serine residues 44-46 was required for efficient SPOP binding and ERG degradation. Treatment with the DNA-damaging agent etoposide stimulated CKI-dependent phosphorylation of TMPRSS2–ERG fusion proteins that harbor a masked SPOP binding site, restoring SPOP binding and ERG degradation and inhibiting ERG-dependent migration in prostate cancer cells with wild-type ERG. These data reveal a tumor-suppressive role for SPOP in the posttranslational regulation of ERG. These findings also suggest previously undefined mechanisms contributing to the elevation of truncated ERG proteins in TMPRSS2–ERG fusion–positive prostate cancer and that etoposide may restore CKIδ–SPOP-mediated ERG regulation in patients with wild-type ERG or specific TMPRSS2–ERG isoforms.
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