Interplay and cooperation between SREBF1 and master transcription factors regulate lipid metabolism and tumor-promoting pathways in squamous cancer.
Interplay and cooperation between SREBF1 and master transcription factors regulate lipid metabolism and tumor-promoting pathways in squamous cancer.
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DOI：
10.1038/s41467-021-24656-x
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发表时间：
2021-07-16
影响因子：
16.6
通讯作者：
Lin DC
中科院分区：
文献类型：
--
作者：
Li LY;Yang Q;Jiang YY;Yang W;Jiang Y;Li X;Hazawa M;Zhou B;Huang GW;Xu XE;Gery S;Zhang Y;Ding LW;Ho AS;Zumsteg ZS;Wang MR;Fullwood MJ;Freedland SJ;Meltzer SJ;Xu LY;Li EM;Koeffler HP;Lin DC
鳞状细胞癌（SCC）是人类癌症中最常见的组织学类型之一。SCC细胞的转录失调是由肿瘤蛋白p63（TP 63），主转录因子（TF）和一个研究充分的SCC特异性癌基因协调的。在本研究中，SCC患者样本的基因集富集分析（GSEA）和体外功能丧失测定都将脂肪酸代谢确立为TP 63下游的关键途径。进一步的研究确定了固醇调节元件结合转录因子1（SREBF 1）作为连接TP 63与脂肪酸代谢的中心介质，其调节脂肪酸、鞘脂（SL）和甘油磷脂（GPL）的生物合成，如基于液相色谱串联质谱（LC-MS/MS）的脂质组学所揭示的。此外，还鉴定了由SREBF 1/TP 63/Kruppel样因子5（KLF 5）组成的反馈共调节环，其促进SCC中所有三种TF的过表达。在SREBF 1下游，阐明了一种非经典的SCC特异性功能：SREBF 1与TP 63/KLF 5合作调节SCC表观基因组中数百个顺式调节元件，这些元件聚集在激活促癌途径上。事实上，SREBF 1对于SCC的存活和迁移是必不可少的，并且其过表达与SCC患者的存活率差相关。总之，这些数据揭示了癌症中转录失调的机制，确定了脂质代谢的特定表观遗传调节因子，并揭示了SREBF 1作为SCC中潜在的治疗靶点和预后标志物。鳞状细胞癌（SCC）表观遗传调控的相关性和潜在的分子机制有待进一步表征。在这里，作者显示了一个涉及SREBF 1，TP 63和KLF 5的转录调控环，通过脂肪酸，ERBB和mTOR通路调控驱动SCC中的肿瘤发生。
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.
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