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

doi:10.1016/j.celrep.2021.108768

CRTC1/MAML2 directs a PGC-1α-IGF-1 circuit that confers vulnerability to PPARγ inhibition

Cell Rep. 2021 Feb 23;34(8):108768. doi: 10.1016/j.celrep.2021.108768.

Authors

Adele M Musicant¹, Kshitij Parag-Sharma², Weida Gong³, Monideepa Sengupta⁴, Arindam Chatterjee⁵, Erin C Henry⁶, Yi-Hsuan Tsai³, Michele C Hayward⁷, Siddharth Sheth⁸, Renee Betancourt⁹, Trevor G Hackman¹⁰, Ricardo J Padilla¹¹, Joel S Parker¹², Jimena Giudice¹³, Colin A Flaveny⁵, David N Hayes¹⁴, Antonio L Amelio¹⁵

Affiliations

¹ 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.
² 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.
³ Bioinformatics Core, Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Graduate Curriculum in Pharmacological and Physiological Sciences, School of Medicine, Saint Louis University, Saint Louis, MO, USA.
⁵ Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, Saint Louis, MO, USA.
⁶ Division of Oral and Craniofacial Health Sciences, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Lineberger Comprehensive Cancer Center, Cancer Genetics Program, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ Division of Hematology/Oncology, Department of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ Department of Pathology and Laboratory Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Department of Otolaryngology/Head and Neck Surgery, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Division of Diagnostic Sciences, UNC Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² 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.
¹³ 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.
¹⁴ 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.
¹⁵ 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. Electronic address: [email protected].

Abstract

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.

Keywords: CRTC1-MAML2; IGF-1 inhibitor; PPARGC1A, IGF-1; cancer; chromosomal translocation; gene fusion; oncogene; transcriptional co-activator.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Autocrine Communication
Carcinoma, Mucoepidermoid / drug therapy*
Carcinoma, Mucoepidermoid / genetics
Carcinoma, Mucoepidermoid / metabolism
Carcinoma, Mucoepidermoid / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Female
Gene Expression Regulation, Neoplastic
Gene Fusion
Humans
Insulin-Like Growth Factor I / genetics
Insulin-Like Growth Factor I / metabolism*
Male
Mice
Mice, Nude
Middle Aged
Molecular Targeted Therapy
PPAR gamma / antagonists & inhibitors*
PPAR gamma / genetics
PPAR gamma / metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
Protein Isoforms
Receptor, IGF Type 1 / antagonists & inhibitors
Receptor, IGF Type 1 / metabolism
Salivary Gland Neoplasms / drug therapy*
Salivary Gland Neoplasms / genetics
Salivary Gland Neoplasms / metabolism
Salivary Gland Neoplasms / pathology
Signal Transduction
Trans-Activators / genetics
Trans-Activators / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Burden / drug effects
Xenograft Model Antitumor Assays

Substances

CRTC1 protein, human
IGF1 protein, human
IGF1R protein, human
MAML2 protein, human
PPAR gamma
PPARG protein, human
PPARGC1A protein, human
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Protein Isoforms
Trans-Activators
Transcription Factors
Insulin-Like Growth Factor I
Receptor, IGF Type 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding