Ismail Houssam, Chagraoui Jalila, Sauvageau Guy
Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Québec, Canada.
Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
Sci Adv. 2025 Jun 6;11(23):eads6556. doi: 10.1126/sciadv.ads6556.
Several landmark studies over the past decade have uncovered a critical role of the CRL3 ubiquitin ligase complex in regulating stability of corepressor of repressor element 1 silencing transcription factor (CoREST) complex proteins and normal hematopoietic stem cell self-renewal. There is now mounting evidence that the CoREST complex plays oncogenic roles, although the contributions of its catalytic versus noncatalytic functions remain unclear. Here, we summarize and discuss mechanisms whereby the CoREST complex coopts tissue-specific transcription factors to elicit pathogenic activity in cancer and neurodegenerative disease. We also identify tumor types with selective dependencies on the scaffolding properties of the CoREST complex. We argue that these tumor types may benefit from a KBTBD4-activating/CoREST complex degrader therapy, which could also enhance antitumor immunity and sensitize resistant tumors to immunotherapy. Overall, understanding how the CoREST complex operates abnormally and differences between its targeting through catalytic inhibitors or protein degraders will help discern all possible applications for targeting therapies now in clinical development.
过去十年中的几项具有里程碑意义的研究揭示了CRL3泛素连接酶复合物在调节阻遏元件1沉默转录因子（CoREST）复合物蛋白的稳定性和正常造血干细胞自我更新方面的关键作用。现在有越来越多的证据表明CoREST复合物具有致癌作用，尽管其催化功能与非催化功能的贡献仍不清楚。在这里，我们总结并讨论了CoREST复合物借助组织特异性转录因子引发癌症和神经退行性疾病致病活性的机制。我们还确定了对CoREST复合物支架特性具有选择性依赖性的肿瘤类型。我们认为，这些肿瘤类型可能受益于KBTBD4激活/CoREST复合物降解疗法，该疗法还可以增强抗肿瘤免疫力并使耐药肿瘤对免疫疗法敏感。总体而言，了解CoREST复合物如何异常运作以及通过催化抑制剂或蛋白质降解剂对其进行靶向的差异，将有助于识别目前临床开发中靶向疗法的所有可能应用。
