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

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. 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.