LSD1 and CoREST2 Potentiate STAT3 Activity to Promote Enteroendocrine Cell Differentiation in Mucinous Colorectal Cancer

Abstract Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EEC), the neuroendocrine cells of the normal colon epithelium, as compared with non-mCRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. In this study, single-cell multiomics uncovered epigenetic alterations that accompany EEC differentiation, identified STAT3 as a regulator of EEC specification, and discovered a rare cancer-specific cell type with enteric neuron–like characteristics. Furthermore, lysine-specific demethylase 1 (LSD1) and CoREST2 mediated STAT3 demethylation and enhanced STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. Collectively, these results provide a rationale for developing LSD1 inhibitors that target the interaction between LSD1 and STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC. Significance: STAT3 activity mediated by LSD1 and CoREST2 induces enteroendocrine cell specification in mucinous colorectal cancer, suggesting disrupting interaction among LSD1, CoREST2, and STAT3 as a therapeutic strategy to target neuroendocrine differentiation.