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

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

doi:10.1158/0008-5472.can-18-0359

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.

Highlights

The STAT3 is a transcription factor found in a constitutive active form in a large number of malignances, including breast, ovarian, pancreatic, gastric cancers, and leukemia, downstream to the aberrant activation of oncoproteins and soluble factors [1,2,3,4]
While STAT3 Tyr705 phosphorylation was uniquely dependent on anaplastic lymphoma kinase (ALK), STAT3 Ser727 phosphorylation and acetylation relied on the Ser/Thr kinases mTOR, PI3K, and MAPK, previously described targets of ALK [30, 31]
We show that STAT3 is constitutively phosphorylated and acetylated in ALKþ cells and anaplastic large-cell lymphomas (ALCL) Patient-derived tumor xenografts (PDTX) and it is bound to the transcriptional repressor complex Sin3A, and that these events are critical for the repression of a number of tumor suppressor genes (TSG) previously reported to be repressed by STAT3 and critical for NPM-ALK tumorigenic potential

Summary

Introduction

The STAT3 is a transcription factor found in a constitutive active form in a large number of malignances, including breast, ovarian, pancreatic, gastric cancers, and leukemia, downstream to the aberrant activation of oncoproteins and soluble factors [1,2,3,4]. ALKþ cell lines and patient samples reveal constitutively activation of STAT3 [9,10,11], which contributes to NPM-ALK–dependent transformation by acting both as transcriptional activator and as transcriptional repressor. While constitutive phosphorylation of STAT3 on Tyr705 sustains the canonical oncogenic role of STAT3 as activator of genes involved in cell proliferation, survival, invasion, and immunosuppression [12, 13], deregulated STAT3 leads to aberrant epigenetic silencing of several tumor suppressor genes (TSG), including genes involved in T-cell identity and apoptosis [14,15,16]. Interfering with STAT3 expression, as well as the treatment with demethylating agents or deacetylases inhibitors, was shown to restore TSG expression and induce apoptosis of ALKþ ALCL cells, underlying the important contribution of STAT3-mediated epigenetic silencing to cell transformation [14, 15, 17, 18]

Methods

Results

Conclusion