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 (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mCRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics 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, 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 rationale for developing LSD1 inhibitors that target the interaction between LSD1 and STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC.

中文翻译：

---

LSD1 和 CoREST2 增强 STAT3 活性以促进粘液性结直肠癌肠内分泌细胞分化


神经内分泌细胞与许多癌症类型的治疗耐药性和较差的总生存期有关。与非 mCRC 相比，粘液性结直肠癌 （mCRC） 在肠内分泌细胞 （EEC） 中具有独特的富集，EEC 是正常结肠上皮的神经内分泌细胞。因此，靶向 EEC 鉴别可能在 mCRC 中具有临床价值。在这里，单细胞多组学揭示了伴随 EEC 分化的表观遗传改变，确定了 STAT3 是 EEC 规范的调节因子，并发现了一种具有肠道神经元样特征的罕见癌症特异性细胞类型。此外，LSD1 和 CoREST2 介导 STAT3 去甲基化并增强 STAT3 染色质结合。在原位异种移植小鼠模型中敲低 CoREST2 导致原发性肿瘤生长和肺转移减少。总的来说，这些结果为开发靶向 LSD1 与 STAT3 或 CoREST2 之间相互作用的 LSD1 抑制剂提供了理论依据，这可能会改善 mCRC 患者的临床预后。