TY - JOUR
T1 - The transcriptional regulator Sin3A contributes to the oncogenic potential of STAT3
AU - Gambi, Giovanni
AU - Di Simone, Elisabetta
AU - Basso, Veronica
AU - Ricci, Luisa
AU - Wang, Rui
AU - Verma, Akanksha
AU - Elemento, Olivier
AU - Ponzoni, Maurilio
AU - Inghirami, Giorgio
AU - Icardi, Laura
AU - Mondino, Anna
PY - 2019/6/15
Y1 - 2019/6/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85067399160&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067399160&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-0359
DO - 10.1158/0008-5472.CAN-18-0359
M3 - Article
C2 - 30692217
AN - SCOPUS:85067399160
VL - 79
SP - 3076
EP - 3087
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 12
ER -