Interplay and cooperation between SREBF1 and master transcription factors regulate lipid metabolism and tumor-promoting pathways in squamous cancer

Li-Yan Li (), Qian Yang, Yan-Yi Jiang, Wei Yang, Yuan Jiang, Xiang Li, Masaharu Hazawa, Bo Zhou, Guo-Wei Huang, Xiu-E Xu, Sigal Gery, Ying Zhang, Ling-Wen Ding, Allen S. Ho, Zachary S. Zumsteg, Ming-Rong Wang, Melissa J. Fullwood, Stephen J. Freedland, Stephen J. Meltzer, Li-Yan Xu (), En-Min Li (), H. Phillip Koeffler and Lin De-Chen ()
Additional contact information
Li-Yan Li: Shantou University Medical College
Qian Yang: Samuel Oschin Cancer Center, Cedars-Sinai Medical Center
Yan-Yi Jiang: Samuel Oschin Cancer Center, Cedars-Sinai Medical Center
Wei Yang: Cedars-Sinai Medical Center
Yuan Jiang: Samuel Oschin Cancer Center, Cedars-Sinai Medical Center
Xiang Li: Shantou University Medical College
Masaharu Hazawa: Kanazawa University
Bo Zhou: Cedars-Sinai Medical Center
Guo-Wei Huang: Samuel Oschin Cancer Center, Cedars-Sinai Medical Center
Xiu-E Xu: Shantou University Medical College
Sigal Gery: Samuel Oschin Cancer Center, Cedars-Sinai Medical Center
Ying Zhang: National University of Singapore
Ling-Wen Ding: National University of Singapore
Allen S. Ho: Samuel Oschin Cancer Center, Cedars-Sinai Medical Center
Zachary S. Zumsteg: Cedars-Sinai Medical Center
Ming-Rong Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Melissa J. Fullwood: National University of Singapore
Stephen J. Freedland: USA and the Durham VA Medical Center
Stephen J. Meltzer: Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center
Li-Yan Xu: Shantou University Medical College
En-Min Li: Shantou University Medical College
H. Phillip Koeffler: Samuel Oschin Cancer Center, Cedars-Sinai Medical Center
Lin De-Chen: Samuel Oschin Cancer Center, Cedars-Sinai Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Squamous cell carcinomas (SCCs) comprise one of the most common histologic types of human cancer. Transcriptional dysregulation of SCC cells is orchestrated by tumor protein p63 (TP63), a master transcription factor (TF) and a well-researched SCC-specific oncogene. In the present study, both Gene Set Enrichment Analysis (GSEA) of SCC patient samples and in vitro loss-of-function assays establish fatty-acid metabolism as a key pathway downstream of TP63. Further studies identify sterol regulatory element binding transcription factor 1 (SREBF1) as a central mediator linking TP63 with fatty-acid metabolism, which regulates the biosynthesis of fatty-acids, sphingolipids (SL), and glycerophospholipids (GPL), as revealed by liquid chromatography tandem mass spectrometry (LC-MS/MS)-based lipidomics. Moreover, a feedback co-regulatory loop consisting of SREBF1/TP63/Kruppel like factor 5 (KLF5) is identified, which promotes overexpression of all three TFs in SCCs. Downstream of SREBF1, a non-canonical, SCC-specific function is elucidated: SREBF1 cooperates with TP63/KLF5 to regulate hundreds of cis-regulatory elements across the SCC epigenome, which converge on activating cancer-promoting pathways. Indeed, SREBF1 is essential for SCC viability and migration, and its overexpression is associated with poor survival in SCC patients. Taken together, these data shed light on mechanisms of transcriptional dysregulation in cancer, identify specific epigenetic regulators of lipid metabolism, and uncover SREBF1 as a potential therapeutic target and prognostic marker in SCC.

Date: 2021
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DOI: 10.1038/s41467-021-24656-x

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