The transcriptional regulator Sin3A contributes to the oncogenic potential of STAT3

Giovanni Gambi, Elisabetta Di Simone, Veronica Basso, Luisa Ricci, Rui Wang, Akanksha Verma, Olivier Elemento, Maurilio Ponzoni, Giorgio Inghirami, Laura Icardi, Anna Mondino

Research output: Contribution to journalArticlepeer-review

Abstract

Epigenetic silencing of promoter and enhancer regions is a common phenomenon inmalignant cells. The transcription factor STAT3 is aberrantly activated in several tumors, where its constitutive acetylation accounts for the transcriptional repressionof anumber of tumor suppressor genes (TSG) via molecular mechanisms that remain to be understood. Using nucleophosmin-anaplastic lymphoma kinase-positive (NPM-ALK+) anaplastic large-cell lymphoma (ALCL) as model system, we found in cells and patient-derived tumor xenografts that STAT3 is constitutively acetylated as a result of ALK activity. STAT3 acetylation relied on intact ALK-induced PI3K- and mTORC1-dependent signaling and was sensitive to resveratrol. Resveratrol lowered STAT3 acetylation, rescued TSG expression, and induced ALCL apoptotic cell death. STAT3 constitutively bound the Sin3A transcriptional repressor complex, and both STAT3 and Sin3A bound the promoter region of silenced TSG via a resveratrol-sensitive mechanism. Silencing SIN3A caused reexpression of TSG, induced ALCL apoptotic cell deathin vitro, and hinderedALCL tumorigenic potential in vivo. A constitutive STAT3-Sin3A interaction was also found in breast adenocarcinoma cells and proved critical for TSG silencing and cell survival. Collectively, these results suggest that oncogenedriven STAT3 acetylation and its constitutive association with Sin3A represent novel and concomitant events contributing to STAT3 oncogenic potential.

Original languageEnglish
Pages (from-to)3076-3087
Number of pages12
JournalCancer Research
Volume79
Issue number12
DOIs
Publication statusPublished - Jun 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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