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.
Highlights
Cancer is characterized by dysregulated metabolic activity leading to enhanced cell growth and proliferation[1,2]
We identified signaling pathways enriched in Squamous cell carcinomas (SCCs) samples with high TP63 expression by analyzing RNASeq data from TCGA cohorts, including ESCC (n = 81), HNSC (n = 436) and LUSC (n = 501) samples
72.8% (182/250) of positively correlated genes identified in ESCC were shared with either LUSC (P < 1E-06) or HNSC (P < 1E-06) cohorts
Summary
Cancer is characterized by dysregulated metabolic activity leading to enhanced cell growth and proliferation[1,2]. To identify putative in vivo TP63-target genes and signaling pathways in pan-SCC patients, in the current study we initially performed Gene Set Enrichment Analysis (GSEA) using SCC patient samples This unbiased analysis identified fatty-acid metabolism as one of the most significantly enriched pathways downstream of TP63 across different types of SCCs. In addition, SREBF1 was pinpointed as the central mediator between TP63 and fatty-acid metabolism. We perform epigenomic, metabolomic and transcriptomic analyses in SCC and elucidate that SREBF1 acts as a central mediator linking TP63 with fatty-acid metabolism. We find that SREBF1 cooperates with TP63/KLF5 to regulate hundreds of cis-regulatory elements across the SCCspecific epigenome, which converges on activating cancerpromoting pathways, uncovering SREBF1 as a potential therapeutic target and prognostic marker in SCC
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