北京大学深圳医院袁林等研究人员合作发现，mTORC2驱动的染色质cGAS通过表观遗传重编程介导结直肠癌的化疗耐药性。相关论文于2024年7月30日在线发表在《自然—细胞生物学》杂志上。

研究人员发现人类环磷酸鸟苷-腺苷酸合成酶（cGAS）的丝氨酸37位点经mTORC2介导的磷酸化促进其在结直肠癌细胞中的染色质定位，而不依赖于STING调节细胞生长和药物耐受性。

研究人员发现，染色质结合的cGAS（ccGAS）在特定的染色质区域招募SWI/SNF复合体，改变了与谷氨酸解毒和DNA复制相关的基因表达。虽然ccGAS的去除抑制了细胞生长，但在体外和体内均引发了对氟尿嘧啶治疗的化学耐药性。

此外，阻断肾型谷氨酸酶（ccGAS的下游靶标）可以克服由ccGAS缺失引起的化学耐药性。因此，ccGAS通过表观遗传图谱协调结直肠癌的可塑性和获得的化学耐药性。靶向mTORC2–ccGAS及谷氨酸酶提供了一种有前景的策略，可用于消除耐药的休眠癌细胞。

据悉，cGAS是一种细胞质DNA传感器，能够启动依赖于STING的先天免疫反应，其与染色质结合紧密，在此过程中其催化活性受到抑制。然而，cGAS招募到染色质上的机制以及ccGAS的功能仍不清楚。

附：英文原文

Title: mTORC2-driven chromatin cGAS mediates chemoresistance through epigenetic reprogramming in colorectal cancer

Author: Lv, Guoqing, Wang, Qian, Lin, Lin, Ye, Qiao, Li, Xi, Zhou, Qian, Kong, Xiangzhen, Deng, Hongxia, You, Fuping, Chen, Hebing, Wu, Song, Yuan, Lin

Issue&Volume: 2024-07-30

Abstract: 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.

DOI: 10.1038/s41556-024-01473-0

Source: https://www.nature.com/articles/s41556-024-01473-0