The Transcriptional Regulator Sin3A Contributes to the Oncogenic Potential of STAT3.

TitleThe Transcriptional Regulator Sin3A Contributes to the Oncogenic Potential of STAT3.
Publication TypeJournal Article
Year of Publication2019
AuthorsGambi G, Di Simone E, Basso V, Ricci L, Wang R, Verma A, Elemento O, Ponzoni M, Inghirami G, Icardi L, Mondino A
JournalCancer Res
Date Published2019 Jun 15
KeywordsAdult, Carcinogenesis, Humans, Lymphoma, Large-Cell, Anaplastic, Oncogenes, Protein-Tyrosine Kinases, STAT3 Transcription Factor

Epigenetic silencing of promoter and enhancer regions is a common phenomenon in malignant cells. The transcription factor STAT3 is aberrantly activated in several tumors, where its constitutive acetylation accounts for the transcriptional repression of a number 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 death , and hindered ALCL tumorigenic potential . 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 oncogene-driven STAT3 acetylation and its constitutive association with Sin3A represent novel and concomitant events contributing to STAT3 oncogenic potential. SIGNIFICANCE: This study delineates the transcriptional regulatory complex Sin3A as a mediator of STAT3 transcriptional repressor activity and identifies the STAT3/Sin3A axis as a druggable target to antagonize STAT3-addicted tumors. GRAPHICAL ABSTRACT:

Alternate JournalCancer Res.
PubMed ID30692217