2. Academic Validation
  3. mTORC2-driven chromatin cGAS mediates chemoresistance through epigenetic reprogramming in colorectal cancer

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

  • Nat Cell Biol. 2024 Jul 30. doi: 10.1038/s41556-024-01473-0.
Guoqing Lv # 1 2,  Qian Wang # 3,  Lin Lin # 4,  Qiao Ye # 5,  Xi Li 1,  Qian Zhou 6,  Xiangzhen Kong 7,  Hongxia Deng 8,  Fuping You 9,  Hebing Chen 4,  Song Wu 10,  Lin Yuan # 11 12
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences, Peking University Shenzhen Hospital, Shenzhen, China.
  • 2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3 Department of Urology, The Third Affiliated Hospital & South China Hospital of Shenzhen University, Shenzhen, China.
  • 4 Institute of Health Service and Transfusion Medicine, Beijing, China.
  • 5 Clinical Medicine Laboratory, Air Force Medical Center, Beijing, China.
  • 6 Department of Computer Science, City University of Hong Kong, Hong Kong, China.
  • 7 Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 8 Department of Otorhinolaryngology Head and Neck Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, China.
  • 9 Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 10 Department of Urology, The Third Affiliated Hospital & South China Hospital of Shenzhen University, Shenzhen, China. wusong@szu.edu.cn.
  • 11 Institute of Biomedical Sciences, Peking University Shenzhen Hospital, Shenzhen, China. yuan_lin@bjmu.edu.cn.
  • 12 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA. yuan_lin@bjmu.edu.cn.
  • # Contributed equally.
PMID: 39080411 DOI: 10.1038/s41556-024-01473-0
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.

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