Upregulation of LRRC8A by m5C modification-mediated mRNA stability suppresses apoptosis and facilitates tumorigenesis in cervical cancer

  • Int J Biol Sci. 2023 Jan 1;19(2):691-704. doi: 10.7150/ijbs.79205.
Yanjie Chen  1 ,  Xinzhao Zuo  1 ,  Qinglv Wei  1 ,  Jie Xu  1 ,  Xiaoyi Liu  1 ,  Shiling Liu  2 ,  Haocheng Wang  1 ,  Qingya Luo  3 ,  Yuya Wang  1 ,  Yu Yang  1 ,  Hongyan Zhao  1  4 ,  Jing Xu  1 ,  Tao Liu  1 ,  Ping Yi  1
Affiliations
  • 1. Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China.
  • 2. Department of Obstetrics and Gynecology, Daping Hospital, Army Medical University, Chongqing 400042, China.
  • 3. Department of Pathology, Southwest Hospital, Army Medical Universtiy, Chongqing 400038, China.
  • 4. Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, China.
PMID: 36632452 DOI: 10.7150/ijbs.79205
Abstract

Cervical Cancer (CC) is one of the most common gynecological malignancies with poor prognosis for advanced CC patients. LRRC8A is a volume-regulated anion channel protein involved in cellular homeostasis, but its role in CC remains largely unknown. In this study, we found that LRRC8A is elevated in CC and associated with poor prognosis. LRRC8A maintains cell survivals under the hypotonic condition, and promotes tumorigenesis through Apoptosis suppression in vitro and in vivo. Notably, LRRC8A is upregulated by NSUN2-mediated m5C modification. m5C modified-LRRC8A mRNA is bound by the RNA binding protein YBX1 followed by the increased RNA stability. Moreover, loss of NSUN2 suppresses the proliferation and metastasis of CC cells, and NSUN2 expression is positively correlated with LRRC8A expression in CC. Altogether, our study demonstrates that the NSUN2-m5C-LRRC8A axis is crucial and would be a potential therapeutic target for CC.

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