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Cancer Res. 2019 Jun 15;79(12):3076-3087. doi: 10.1158/0008-5472.CAN-18-0359. Epub 2019 Jan 28.

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

Author information

1
Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milan, Italy.
2
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
3
Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
4
Institute for Precision Medicine, Weill Cornell Medical College, New York, New York.
5
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York.
6
Department of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
7
Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies (CeRMS), University of Turin, Turin, Italy.
8
Department of Pathology and NYU Cancer Center, New York University School of Medicine, New York, New York.
9
Division of Immunology, Transplantation and Infectious Disease, IRCCS San Raffaele Scientific Institute, Milan, Italy. mondino.anna@hsr.it icardi.laura@hsr.it.
#
Contributed equally

Abstract

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 in vitro, and hindered ALCL 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 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: http://cancerres.aacrjournals.org/content/canres/79/12/3076/F1.large.jpg.See related commentary by Monteleone and Poli, p. 3031.

PMID:
30692217
DOI:
10.1158/0008-5472.CAN-18-0359
[Indexed for MEDLINE]

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