环 GMP-AMP 合酶 (cGAS) 是一种胞质 DNA 传感器，可启动 STING 依赖性先天免疫反应，与染色质紧密结合，其催化活性受到抑制；然而，cGAS 招募至染色质的机制以及染色质结合 cGAS (ccGAS) 的功能仍不清楚。在这里，我们发现 mTORC2 介导的人 cGAS 丝氨酸 37 的磷酸化促进其染色质在结直肠癌细胞中的定位，独立于 STING 调节细胞生长和耐药性。我们发现 ccGAS 在特定染色质区域招募 SWI/SNF 复合物，从而改变与谷氨酰胺分解和 DNA 复制相关的基因表达。尽管 ccGAS 消耗抑制了细胞生长，但它在体外和体内诱导了对氟尿嘧啶治疗的化学耐药性。此外，阻断肾型谷氨酰胺酶（ccGAS 下游靶标）克服了 ccGAS 损失引起的化疗耐药性。因此，ccGAS 协调结直肠癌的可塑性并通过表观遗传模式获得化疗耐药性。针对 mTORC2-ccGAS 和谷氨酰胺酶提供了一种消除静态耐药癌细胞的有前景的策略。© 2024。作者。

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor that initiates a STING-dependent innate immune response, binds tightly to chromatin, where its catalytic activity is inhibited; however, mechanisms underlying cGAS recruitment to chromatin and functions of chromatin-bound cGAS (ccGAS) remain unclear. Here we show that mTORC2-mediated phosphorylation of human cGAS serine 37 promotes its chromatin localization in colorectal cancer cells, regulating cell growth and drug resistance independently of STING. We discovered that ccGAS recruits the SWI/SNF complex at specific chromatin regions, modifying expression of genes linked to glutaminolysis and DNA replication. Although ccGAS depletion inhibited cell growth, it induced chemoresistance to fluorouracil treatment in vitro and in vivo. Moreover, blocking kidney-type glutaminase, a downstream ccGAS target, overcame chemoresistance caused by ccGAS loss. Thus, ccGAS coordinates colorectal cancer plasticity and acquired chemoresistance through epigenetic patterning. Targeting both mTORC2-ccGAS and glutaminase provides a promising strategy to eliminate quiescent resistant cancer cells.© 2024. The Author(s).