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

Wan Chang1, Qingyu Luo1, Xiaowei Wu1

  • 1State 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.

Cell Reports
|October 26, 2022
PubMed

Insights

DNA hypermethylation of otubain 2 (OTUB2) drives oral and esophageal squamous cell carcinomas (SCCs). Soybean-derived phosphatidylserine (PS) shows potential for SCC prevention and treatment by inhibiting tumor initiation and enhancing chemotherapy sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Oral and esophageal squamous cell carcinomas (SCCs) have high mortality rates.
  • The molecular drivers of SCC development and drug resistance remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying oral and esophageal SCC initiation and drug resistance.
  • To investigate the potential of phosphatidylserine (PS) as a therapeutic and preventative agent for SCCs.

Main Methods:

  • Analysis of DNA hypermethylation of otubain 2 (OTUB2) in SCCs.
  • Investigated the role of OTUB2 in deubiquitination and phosphorylation of signal transducer and activator of transcription 1 (STAT1).
  • Examined the regulation of calmodulin-like protein 3 (CALML3) and its downstream effects on mitochondrial calcium signaling, oxidative phosphorylation (OXPHOS), and PS synthesis in mouse models.

Main Results:

  • DNA hypermethylation of OTUB2 was identified as a driver of SCC initiation and drug resistance.
  • OTUB2 activates the STAT1/CALML3 pathway, promoting OXPHOS and PS synthesis.
  • Orally administered soybean-derived PS inhibited SCC initiation and sensitized chemotherapy in mouse models with low OTUB2 expression.

Conclusions:

  • The OTUB2/STAT1/CALML3/PS axis plays a tumor-suppressive role in SCCs.
  • Phosphatidylserine (PS) administration represents a promising therapeutic and preventative strategy for tongue and esophageal SCCs.
Keywords:
CALML3CP: CancerOTUB2OXPHOSSTAT1calcium signalingchemoresistancelipid metabolismphosphatidylserinesquamous cell carcinomatumorigenesis

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