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

• Published in: Nature communications Vol. 12; no. 1; pp. 4362 - 17
• Main Authors: Li, Li-Yan, Yang, Qian, Jiang, Yan-Yi, Yang, Wei, Jiang, Yuan, Li, Xiang, Hazawa, Masaharu, Zhou, Bo, Huang, Guo-Wei, Xu, Xiu-E, Gery, Sigal, Zhang, Ying, Ding, Ling-Wen, Ho, Allen S., Zumsteg, Zachary S., Wang, Ming-Rong, Fullwood, Melissa J., Freedland, Stephen J., Meltzer, Stephen J., Xu, Li-Yan, Li, En-Min, Koeffler, H. Phillip, Lin, De-Chen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.07.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/44; 13/51; 13/89; 14/105; 14/19; 38/88; 38/91; 45/77; 49/15; 49/23; 631/208; 631/67/1813/1352; 631/67/68/2486; 64/60; 82/80; Biosynthesis; Cancer; Epigenetics; ErbB protein; Fatty acids; Gene set enrichment analysis; Humanities and Social Sciences; Krueppel-like factor; Lipid metabolism; Lipids; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Metabolism; Molecular modelling; multidisciplinary; Regulatory sequences; Science; Science (multidisciplinary); Sphingolipids; Squamous cell carcinoma; Therapeutic targets; TOR protein; Transcription factors; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24656-x

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. The relevance and underlying molecular mechanisms of epigenetic regulation in squamous cell carcinomas (SCC) await further characterization. Here, the authors show a transcriptional regulatory loop involving SREBF1, TP63 and KLF5 driving tumourigenesis in SCC through fatty acid, ERBB and mTOR pathway regulation.