LSD1 Promotes EMT via AKT in PIK3CA-Mutant CRC
Miller et al. Page 264
Epithelial–mesenchymal transition (EMT) is a multistep process underlying the metastatic spread of cancers and the regulation of EMT signaling in different tissues of origin is an active area of research. However, the contribution of epigenetic modifications to EMT signaling is poorly understood. In this study, Miller and colleagues demonstrate a role for lysine-specific demethylase 1 (LSD1), which is overexpressed in colorectal cancer, in regulating EMT signaling via AKT. Colorectal cancer tumors with PIK3CA mutations were shown to be acutely reliant on LSD1 expression but independent of its demethylase activity: in these tumors, LSD1 served as a scaffold to facilitate formation of the CoREST transcriptional repressive complex, which ultimately resulted in AKT-mediated stabilization of the EMT-promoting transcription factor Snail. Concordantly, loss of LSD1 expression via CRISPR/Cas9 or RNAi resulted in proteasomal degradation of Snail and tempering of the migratory phenotype. Taken together, the data support a model in which targeting this axis could lead to slower spread of colorectal cancer tumors.
SRSF2 Regulates MDM2 Splicing
Comiskey Jr et al. Page 194
Regulation of p53 stability by the E3 ligase MDM2 is a well-known mechanism underlying cancer cell survival, and disruption of this axis may hold promise in modulating the cellular response to genotoxic therapies. Here, Comiskey and colleagues reveal new insights into the regulation of MDM2 mRNA at the post-transcriptional level by members of the SRSF splicing factor family. Whereas SRSF1 is known to promote MDM2 exon 11 skipping resulting in increased p53 expression, SRSF2 antagonized this alternative splicing event and reduced p53 expression. Notably, SRSF2 regulation was targeted using antisense oligonucleotides to modulate MDM2 splicing, leading to an enhanced apoptotic response. The authors suggest that exploiting this splicing event may represent a tool to modulate p53 activity and, by extension, the cellular response to genotoxic treatment modalities.
CARMIL3 Regulates Tumor Metastasis
Wang et al. Page 240
Cytoskeletal organization and cell adhesions provide key signals to tumor cells that regulate their motility and metastatic spread, but these interactions and the cellular players that regulate them are not fully defined. In this study, Wang and colleagues describe a role for Capping protein Regulator and Myosin 1 Linker 3 (CARMIL3) in regulating these signals. Specifically, using immunoprecipitation-mass spectrometry, CARMIL3 was shown to interact with the actin cytoskeleton via regulating the formation and stability of both focal adhesions and adherens junctions. Gain of CARMIL3 in breast cancer cells was shown to promote a migratory and invasive phenotyp. in vitro, supporting the observation that breast and prostate tumors bearing high CARMIL3 expression are prone to worse outcomes. These data position CARMIL3 as a key regulator of the metastatic cascade and nominate its interactions with the adhesion machinery as potential targets for therapeutic exploitation.
Glutamine Regulates PD-L1 in RCC
Ma et al. Page 324
Programmed death-ligand 1 (PD-L1) expression on tumor cells is a major hurdle to the formation and maintenance of a durable antitumor immune response, but the mechanisms underlying its expression are poorly understood. Here, Ma and colleagues define a novel role for glutamine in modifying PD-L1 expression in renal cell carcinoma (RCC) cells. Though RCC cell lines express differing steady-state levels of PD-L1, glutamine deprivation commonly caused an increase in PD-L1 surface expression. Mechanistically, this change in PD-L1 was shown to occur downstream of hyperactivated EGFR signaling in response to the metabolic demands imposed by glutamine deprivation, and was reliant on ERK1/2 and c-Jun. Chemical inhibition of EGFR/ERK/Jun pathway constituents all blocked the upregulation of PD-L1, thus providing preclinical data supporting a potential role for EGFR pathway inhibitors in modulating the response to immunotherapy in RCC.