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A Long Non-Coding RNA LINC00094 Regulates the Transcriptional Expression of Lipid Metabolism-Related Genes as a New Member of Core Regulatory Circuitry in Esophageal Squamous Cell Carcinoma
57 Pages Posted: 7 Jul 2024
More...Abstract
LINC00094 as a new supper-enhancer (SE)-related long non-coding RNA is associated with poor overall survival of patients with esophageal squamous cell carcinoma (ESCC). However, the transcriptional regulatory mechanism of LINC00094 and the molecular mechanisms by which LINC00094 affects the phenotype of ESCC remains unclear. Here, we found that LINC00094 promoted the proliferation of ESCC cells both in vitro and in vivo. LINC00094 knockdown significantly reduced the expression profiles of transcription activators including transcription factor 3 (TCF3) and Kruppel like factor 5 (KLF5) and lipid metabolism-related genes. Mechanically, TCF3 and KLF5 formed a core regulatory circuitry (CRC) that bound to the SEs of LINC00094 and to their own SEs to regulate the transcriptional expression in a positive feedback loop. Furthermore, RNA-binding protein immunoprecipitation (RIP) assay and RNA pull-down assay demonstrated that LINC00094 interacted with both TCF3 and KLF5. LINC00094 knockdown or RNaseA treatment blocked the complex formation between TCF3 and KLF5. LINC00094 recruited TCF3 and KLF5 to form a ternary complex, which forms a new CRC with TCF3 and KLF5 that regulated its own transcription as well as lipid metabolism-related genes. Knockdown of any or all three genes inhibited the expression of genes related to lipid synthesis and consistently reduced total lipid droplet levels. Treatment with SEs inhibitors (THZ1 and JQ1) effectively inhibited the formation of this CRC and the production of lipid droplets in ESCC cells. The high-risk group of CRC-associated signatures were closely associated with poor prognosis in patients with ESCC. Our findings suggest that LINC00094 is involved in the CRC by forming a complex with TCF3 and KLF5, and this regulation model can affect the phenotype of ESCC cells by controlling the expression of lipid metabolism-related genes.
Funding: This study was supported by grants from the National Cohort of Esophageal Cancer of China Grant No. 2016YFC0901400 [Li-Yan Xu], the National Natural Science Foundation of China Grant No. 81572341[Chun-Quan Li], 2020 Li Ka Shing Foundation Cross-Disciplinary Research Grant No. 2020LKSFG07B [En-Min Li], the National Natural Science Foundation of Guangdong Province, Grant No. 2022A1515010058 [Liu Peng].
Declaration of Interest: The authors declare that they have no competing interests.
Ethical Approval: Ethical consent was approved by the Committees for Ethical Review of Research involving Human Subjects at Shantou University Medical College, approval number is SUMC-2021-68. Written informed consent was obtained from each patient before sample collection. The animal experiments were approved by the Use Committee for Animal Care at Shantou University Medical College, approval number is SUMC-2021338.
Keywords: lncRNA, super-enhancer, esophageal squamous cell carcinoma, core regulatory circuitry, lipid metabolism
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