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EZH2 promotes progression of small cell lung cancer by suppressing the TGF-β-Smad-ASCL1 pathway

Fumihiko Murai1, Daizo Koinuma1, Aya Shinozaki-Ushiku2

  • 1Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku , Tokyo, Japan.

Cell Discovery
|July 28, 2016
PubMed

Insights

Small cell lung cancer cells show low TGF-β type II receptor (TβRII) expression due to EZH2. Restoring TβRII induces apoptosis, suppressing tumor growth by inhibiting the TGF-β-Smad-ASCL1 survival pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Transforming growth factor-β (TGF-β) is a known tumor suppressor that induces apoptosis in cancer cells.
  • Small cell lung cancer (SCLC) survival mechanisms are not fully understood, particularly regarding TGF-β signaling.
  • Dysregulation of TGF-β signaling is implicated in various cancers, but its role in SCLC requires further elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms regulating survival in small cell lung cancer cells.
  • To identify the role of TGF-β signaling and its receptor, TβRII, in SCLC.
  • To elucidate the interplay between EZH2, TβRII expression, and TGF-β-mediated apoptosis in SCLC.

Main Methods:

  • Functional analysis of TGF-β signaling pathway in SCLC cells.
  • Quantitative assessment of TβRII expression in SCLC cells and tissues versus normal lung tissues.
  • Overexpression of wild-type TβRII in SCLC cells.
  • Analysis of Polycomb Repressive Complex 2 (PRC2) components, including EZH2, and their impact on TβRII expression.
  • Investigation of ASCL1 (ASH1) as a Smad-dependent target of TGF-β.

Main Results:

  • Most SCLC cells and tissues exhibit significantly lower TGF-β type II receptor (TβRII) expression compared to normal lung cells and tissues.
  • Overexpression of TβRII in SCLC cells restores TGF-β's tumor-suppressive functions, inhibiting cell growth and tumor formation via apoptosis induction.
  • High expression of EZH2 in SCLC cells leads to epigenetic silencing of TβRII, thereby suppressing TGF-β-mediated apoptosis.
  • ASCL1, a TGF-β target, promotes SCLC cell survival.

Conclusions:

  • EZH2 promotes SCLC progression by epigenetically silencing TβRII, thus inhibiting TGF-β-induced apoptosis.
  • The TGF-β-Smad-ASCL1 pathway is suppressed in SCLC by EZH2-mediated TβRII silencing.
  • Restoring TβRII expression or reactivating TGF-β signaling may represent a therapeutic strategy for SCLC.
Keywords:
ASCL1EZH2SmadTGF-βapoptosisepigeneticssmall cell lung cancer

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