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CRTC1/MAML2 directs a PGC-1α-IGF-1 circuit that confers vulnerability to PPARγ inhibition.
Musicant, Adele M; Parag-Sharma, Kshitij; Gong, Weida; Sengupta, Monideepa; Chatterjee, Arindam; Henry, Erin C; Tsai, Yi-Hsuan; Hayward, Michele C; Sheth, Siddharth; Betancourt, Renee; Hackman, Trevor G; Padilla, Ricardo J; Parker, Joel S; Giudice, Jimena; Flaveny, Colin A; Hayes, David N; Amelio, Antonio L.
Afiliación
  • Musicant AM; Graduate Curriculum in Genetics and Molecular Biology, Biological and Biomedical Sciences Program, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Parag-Sharma K; Graduate Curriculum in Cell Biology and Physiology, Biological and Biomedical Sciences Program, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Gong W; Bioinformatics Core, Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Sengupta M; Graduate Curriculum in Pharmacological and Physiological Sciences, School of Medicine, Saint Louis University, Saint Louis, MO, USA.
  • Chatterjee A; Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, Saint Louis, MO, USA.
  • Henry EC; Division of Oral and Craniofacial Health Sciences, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Tsai YH; Bioinformatics Core, Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Hayward MC; Lineberger Comprehensive Cancer Center, Cancer Genetics Program, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Sheth S; Division of Hematology/Oncology, Department of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Betancourt R; Department of Pathology and Laboratory Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Hackman TG; Department of Otolaryngology/Head and Neck Surgery, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Padilla RJ; Division of Diagnostic Sciences, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Parker JS; Lineberger Comprehensive Cancer Center, Cancer Genetics Program, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Giudice J; Department of Cell Biology and Physiology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; McAllister Heart Institute, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Flaveny CA; Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, Saint Louis, MO, USA.
  • Hayes DN; Lineberger Comprehensive Cancer Center, Cancer Genetics Program, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medical Oncology, University of Tennessee Health Sciences West Cancer Center, Memphis, TN, USA.
  • Amelio AL; Division of Oral and Craniofacial Health Sciences, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Cell Biology and Physiology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Biomedical Resear
Cell Rep ; 34(8): 108768, 2021 02 23.
Article en En | MEDLINE | ID: mdl-33626346
Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by a transcriptional coactivator fusion composed of cyclic AMP-regulated transcriptional coactivator 1 (CRTC1) and mastermind-like 2 (MAML2). The mechanisms by which the chimeric CRTC1/MAML2 (C1/M2) oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that C1/M2 induces transcriptional activation of the non-canonical peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) splice variant PGC-1α4, which regulates peroxisome proliferator-activated receptor gamma (PPARγ)-mediated insulin-like growth factor 1 (IGF-1) expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. C1/M2-positive tumors exhibit IGF-1 pathway activation, and small-molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1 receptor (IGF-1R) inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARγ inhibition with inverse agonists. These results yield insights into the aberrant coregulatory functions of C1/M2 and identify a specific vulnerability that can be exploited for precision therapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Factor I del Crecimiento Similar a la Insulina / Neoplasias de las Glándulas Salivales / Protocolos de Quimioterapia Combinada Antineoplásica / Transactivadores / Carcinoma Mucoepidermoide / PPAR gamma Tipo de estudio: Prognostic_studies Idioma: En Revista: Cell Rep Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Factor I del Crecimiento Similar a la Insulina / Neoplasias de las Glándulas Salivales / Protocolos de Quimioterapia Combinada Antineoplásica / Transactivadores / Carcinoma Mucoepidermoide / PPAR gamma Tipo de estudio: Prognostic_studies Idioma: En Revista: Cell Rep Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos