在mTORC2驱动的染色体cGAS通过表观遗传重编程在结直肠癌中调解化学抵抗
Guoqing Lv1,2, Qian Wang3, Lin Lin4
1Institute of Biomedical Sciences, Peking University Shenzhen Hospital, Shenzhen, China.
Nature cell biology
|July 30, 2024
概括
染色体结合cGAS (ccGAS) 通过表观遗传模式调节结直肠癌细胞生长和耐药性. 向mTORC2-ccGAS和谷氨酸酶可以在癌症治疗中克服化疗抵抗.
科学领域:
- 癌症生物学 癌症生物学
- 免疫学 免疫学 免疫学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 循环GMP-AMP合成酶 (cGAS) 是一种细胞质DNA传感器,通过STING启动先天免疫.
- 对于cGAS染色质招募的机制和染色质结合的cGAS (ccGAS) 的功能,尚不完全了解.
- cGAS与染色素结合,其活性被抑制,这表明除了STING之外的调节作用.
研究的目的:
- 阐明cGAS染色体定位的机制和ccGAS在结肠直肠癌中的功能.
- 研究ccGAS在调节癌细胞生长,耐药性和表观遗传修饰方面的作用.
- 确定针对ccGAS及其下游途径的潜在治疗策略.
主要方法:
- 研究了mTORC2介导的人类cGAS在血清37的酸化,以确定其在染色质定位中的作用.
- 研究了ccGAS对特定染色体区域的SWI/SNF复合物的招募.
- 在体外和体内评估了ccGAS枯竭对结直肠癌细胞生长,化学抵抗 (甲) 和基因表达 (谷氨酸溶解,DNA复制) 的影响.
主要成果:
- 通过mTORC2介导的cGAS在37血清中的酸化促进了其在结直肠癌细胞中的染色素定位,独立于STING.
- ccGAS招募SWI/SNF复合体,改变参与谷氨酸溶解和DNA复制的基因的表达.
- ccGAS枯竭抑制了细胞生长,但矛盾的是,它诱导了对甲的化学抵抗,通过阻断脏类型的谷氨酸酶来克服这种抵抗.
结论:
- ccGAS在协调结直肠癌细胞可塑性和通过表观遗传模式获得的化学抵抗方面发挥着关键作用.
- ccGAS调节癌细胞生长和药物耐药性,独立于STING途径.
- 向mTORC2-ccGAS和谷氨酸酶是一个有前途的治疗策略,可以消除耐药癌细胞.
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