2. Academic Validation
  3. OTUB2 exerts tumor-suppressive roles via STAT1-mediated CALML3 activation and increased phosphatidylserine synthesis

OTUB2 exerts tumor-suppressive roles via STAT1-mediated CALML3 activation and increased phosphatidylserine synthesis

  • Cell Rep. 2022 Oct 25;41(4):111561. doi: 10.1016/j.celrep.2022.111561.
Wan Chang 1,  Qingyu Luo 1,  Xiaowei Wu 1,  Yabing Nan 1,  Pengfei Zhao 1,  Lingqiang Zhang 2,  Aiping Luo 1,  Wenjie Jiao 3,  Qiong Zhu 2,  Yesheng Fu 2,  Zhihua Liu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
  • 2 State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China.
  • 3 Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Shandong 266000, China.
  • 4 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address: liuzh@cicams.ac.cn.
PMID: 36288705 DOI: 10.1016/j.celrep.2022.111561
Abstract

Oral and esophageal squamous cell carcinomas (SCCs) are associated with high mortality, yet the molecular mechanisms underlying these malignancies are largely unclear. We show that DNA hypermethylation of otubain 2 (OTUB2), a previously recognized oncogene, drives tongue and esophageal SCC initiation and drug resistance. Mechanistically, OTUB2 promotes the deubiquitination and phosphorylation of signal transducer and activator of transcription 1 (STAT1) and subsequently regulates the transcription of calmodulin-like protein 3 (CALML3). Activation of CALML3-mediated mitochondrial calcium signaling promotes oxidative phosphorylation (OXPHOS) and the synthesis of phosphatidylserine (PS). In mouse models, orally administered soybean-derived PS inhibits SCC initiation in cells with low OTUB2 expression and increases their sensitivity to chemotherapy. Our study indicates that the OTUB2/STAT1/CALML3/PS axis plays tumor-suppressive roles and shows the potential of PS administration as a strategy for the treatment and prevention of tongue and esophageal SCCs.

Keywords

CALML3; CP: Cancer; OTUB2; OXPHOS; STAT1; calcium signaling; chemoresistance; lipid metabolism; phosphatidylserine; squamous cell carcinoma; tumorigenesis.

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