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DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells

Joo-Young Im1, Bo-Kyung Kim2, Kang-Woo Lee3

  • 1Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Korea. imjy@kribb.re.kr.

Oncogenesis
|January 5, 2020
PubMed

Insights

DNA damage-induced apoptosis suppressor (DDIAS) prevents protein tyrosine phosphatase receptor mu (PTPRM) from dephosphorylating STAT3. This sustains STAT3 activation, promoting lung cancer malignancy and offering potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Oncology
  • Signal Transduction

Background:

  • DNA damage-induced apoptosis suppressor (DDIAS) is implicated in cancer cell survival.
  • Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is common in malignant cancers.
  • The precise role of DDIAS in IL-6-mediated STAT3 signaling in lung cancer remains unclear.

Purpose of the Study:

  • To investigate the mechanism by which DDIAS influences IL-6-mediated STAT3 signaling in lung cancer.
  • To identify novel regulators of STAT3 phosphorylation and dephosphorylation in the context of DDIAS function.
  • To explore the potential of DDIAS as a biomarker and therapeutic target in lung cancer.

Main Methods:

  • siRNA screening of protein tyrosine phosphatases (PTPs) to identify STAT3 PTPs.
  • Western blotting and co-immunoprecipitation assays to assess protein interactions and phosphorylation.
  • Analysis of DDIAS and STAT3 phosphorylation in human lung cancer cell lines and tissues.

Main Results:

  • Protein tyrosine phosphatase receptor mu (PTPRM) was identified as a novel STAT3 phosphatase.
  • DDIAS was found to promote STAT3 Y705 phosphorylation by hindering the interaction between PTPRM and STAT3.
  • DDIAS binds to the STAT3 transactivation domain, competing with PTPRM and blocking STAT3 dephosphorylation.
  • DDIAS expression positively correlates with STAT3 phosphorylation in lung cancer samples.

Conclusions:

  • DDIAS sustains STAT3 activation in lung cancer by preventing PTPRM-mediated dephosphorylation.
  • DDIAS acts as a crucial regulator in the IL-6/STAT3 signaling pathway, contributing to lung cancer malignancy.
  • DDIAS represents a potential therapeutic target and biomarker for lung cancers with aberrant STAT3 activation.

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