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STAT3 activates MSK1-mediated histone H3 phosphorylation to promote NFAT signaling in gastric carcinogenesis

Hongyan Qi1, Zhiyi Yang2, Chujun Dai2

  • 1Department of Pathology and Pathophysiology, and Department of Radiation Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.

Oncogenesis
|February 12, 2020
PubMed

Insights

STAT3 signaling drives gastric cancer by activating MSK1, which regulates NFATc2. Targeting this STAT3/MSK1/NFATc2 axis offers a new strategy for gastric cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Epigenetic changes are crucial in gastric cancer development.
  • The regulatory networks linking oncogenic pathways to epigenetic dysregulation are not fully understood.

Purpose of the Study:

  • To elucidate the role of STAT3 signaling in gastric carcinogenesis.
  • To identify downstream targets and mechanisms of STAT3-mediated epigenetic dysregulation.
  • To evaluate the therapeutic potential of targeting the identified signaling axis.

Main Methods:

  • Investigated STAT3 signaling in carcinogen-induced gastric tumorigenesis.
  • Assessed the interaction and function of STAT3, MSK1, and NFATc2.
  • Utilized molecular assays to analyze histone phosphorylation (H3S10) and gene transcription.
  • Evaluated the effect of inhibiting the STAT3/MSK1/NFATc2 axis on gastric cancer cell proliferation and tumor growth in vivo.

Main Results:

  • STAT3 signaling aberrantly activates MSK1, leading to H3S10 phosphorylation and STAT3 phosphorylation.
  • Identified NFATc2 as a downstream target regulated by the STAT3-MSK1 complex via H3S10 phosphorylation.
  • Disruption of the STAT3/MSK1/NFATc2 axis significantly inhibited gastric cancer cell proliferation and xenograft tumor growth.

Conclusions:

  • STAT3 acts as a control pathway in gastric carcinogenesis by linking inflammation to epigenetic dysregulation.
  • The STAT3-MSK1-NFATc2 axis represents a novel regulatory mechanism in gastric cancer.
  • Targeting the STAT3/MSK1/NFATc2 signaling pathway provides a potential therapeutic strategy for gastric cancer.

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