CRTC1/MAML2 directs a PGC-1α-IGF-1 circuit that confers vulnerability to PPARγ inhibition
Adele M. Musicant,
Kshitij Parag-Sharma,
Weida Gong,
Monideepa Sengupta,
Arindam Chatterjee,
Erin C. Henry,
Yi-Hsuan Tsai,
Michele C. Hayward,
Siddharth Sheth,
Renee Betancourt,
Trevor G. Hackman,
Ricardo J. Padilla,
Joel S. Parker,
Jimena Giudice,
Colin A. Flaveny,
David N. Hayes,
Antonio L. Amelio
Affiliations
Adele M. Musicant
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
Kshitij Parag-Sharma
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
Weida Gong
Bioinformatics Core, Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Monideepa Sengupta
Graduate Curriculum in Pharmacological and Physiological Sciences, School of Medicine, Saint Louis University, Saint Louis, MO, USA
Arindam Chatterjee
Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, Saint Louis, MO, USA
Erin C. Henry
Division of Oral and Craniofacial Health Sciences, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Yi-Hsuan Tsai
Bioinformatics Core, Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Michele C. Hayward
Lineberger Comprehensive Cancer Center, Cancer Genetics Program, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Siddharth Sheth
Division of Hematology/Oncology, Department of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Renee Betancourt
Department of Pathology and Laboratory Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Trevor G. Hackman
Department of Otolaryngology/Head and Neck Surgery, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Ricardo J. Padilla
Division of Diagnostic Sciences, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Joel S. Parker
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
Jimena Giudice
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
Colin A. Flaveny
Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, Saint Louis, MO, USA
David N. Hayes
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
Antonio L. Amelio
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 Research Imaging Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, Cancer Cell Biology Program, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Corresponding author
Summary: 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.
