Super Enhancer-Regulated LINC00094 (SERLOC) Upregulates the Expression of MMP-1 and MMP-13 and Promotes Invasion of Cutaneous Squamous Cell Carcinoma

Abstract

Long non-coding RNAs (lncRNAs) have emerged as important regulators of cancer progression. Super enhancers (SE) play a role in tumorigenesis and regulate the expression of specific lncRNAs. We examined the role of <i>BRD3OS</i>, also named <i>LINC00094</i>, in cutaneous squamous cell carcinoma (cSCC). Elevated <i>BRD3OS</i> (<i>LINC00094</i>) expression was detected in cSCC cells, and expression was downregulated by SE inhibitors THZ1 and JQ1 and via the MEK1/ERK1/2 pathway. Increased expression of <i>BRD3OS</i> (<i>LINC00094</i>) was noted in tumor cells in cSCCs and their metastases compared to normal skin, actinic keratoses, and cSCCs in situ. Higher <i>BRD3OS</i> (<i>LINC00094</i>) expression was noted in metastatic cSCCs than in non-metastatic cSCCs. RNA-seq analysis after <i>BRD3OS</i> (<i>LINC00094</i>) knockdown revealed significantly regulated GO terms <i>Cell-matrix adhesion</i>, <i>Basement membrane</i>, <i>Metalloendopeptidase activity</i>, and KEGG pathway <i>Extracellular matrix-receptor interaction.</i> Among the top-regulated genes were <i>MMP1</i>, <i>MMP10</i>, and <i>MMP13</i>. Knockdown of <i>BRD3OS</i> (<i>LINC00094</i>) resulted in decreased production of MMP-1 and MMP-13 by cSCC cells, suppressed invasion of cSCC cells through collagen I, and growth of human cSCC xenografts in vivo. Based on these observations, <i>BRD3OS</i> (<i>LINC00094</i>) was named <i>SERLOC</i> (super enhancer and ERK1/2-Regulated Long Intergenic non-protein coding transcript Overexpressed in Carcinomas). These results reveal the role of <i>SERLOC</i> in cSCC invasion and identify it as a potential therapeutic target in advanced cSCC.