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

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.

TGF-β1 Promotes Autophagy and Inhibits Apoptosis in Breast Cancer by Targeting TP63

“…A large number of studies have reported that TP63 can be used as a prognostic factor for cancers such as salivary gland adenoid cystic carcinoma, anaplastic large cell lymphoma, and squamous cell carcinoma ( 55 – 58 ). The following analysis demonstrated that TP63 as an autophagy-related gene is a low-risk factor for the prognosis of breast cancer, that is, the lower the expression of TP63, the worse the prognosis of breast cancer.…”

Fatty Acid Synthase Is the Key Regulator of Fatty Acid Metabolism and Is Related to Immunotherapy in Bladder Cancer

“…Regulation analysis of FASN provides us more methods to modify fatty acid metabolism in BC ( Figure 8B ). Importantly, the TF most significantly involved in FASN regulation, SREBF1, also plays an important role in lipid metabolism ( 45 , 46 ). Recent studies also reported that multiple lncRNAs competitively bind miRNAs to regulate FASN expression in nasopharyngeal and endometrial cancer ( 47 , 48 ).…”

Deciphering the heterogeneous niche in the tumor progression of hepatocellular carcinoma: a Spatial single-cell landscape and multi-omics atlas analysis

“…Subsequent GRN analysis showed that endothelial cells were regulated by SREBF1, ZNF585A, and HOXB5, and the remarkable expression of exosome marker genes was observed in both malignant and endothelial cell subpopulations. Among them, SREBF1 appears to be associated with cancer [45] but is rarely reported in HCC, All rights reserved. No reuse allowed without permission.…”

“…Subsequent GRN analysis showed that endothelial cells were regulated by SREBF1, ZNF585A, and HOXB5, and the remarkable expression of exosome marker genes was observed in both malignant and endothelial cell subpopulations. Among them, SREBF1 appears to be associated with cancer [45] but is rarely reported in HCC, whereas HOXB5 promotes HCC metastasis by targeting FGFR4 and CXCL1 [46] . HCC-derived exosomes are the main drivers of pre-metastatic ecotone formation and can mediate the metastasis of tumor cells to specific organs [47, 48] .…”