The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor

Abstract

The MITF and SOX10 transcription factors regulate the expression of genes important for melanoma proliferation, invasion and metastasis. Despite growing evidence of the contribution of long noncoding RNAs (lncRNAs) in cancer, including melanoma, their functions within MITF-SOX10 transcriptional programmes remain poorly investigated. Here we identify 245 candidate melanoma associated lncRNAs whose loci are co-occupied by MITF-SOX10 and that are enriched at active enhancer-like regions. Our work suggests that one of these, Disrupted In Renal Carcinoma 3 (DIRC3), may be a clinically important MITF-SOX10 regulated tumour suppressor. DIRC3 depletion in human melanoma cells leads to increased anchorage-independent growth, a hallmark of malignant transformation, whilst melanoma patients classified by low DIRC3 expression have decreased survival. DIRC3 is a nuclear lncRNA that activates expression of its neighbouring IGFBP5 tumour suppressor through modulating chromatin structure and suppressing SOX10 binding to putative regulatory elements within the DIRC3 locus. In turn, DIRC3 dependent regulation of IGFBP5 impacts the expression of genes involved in cancer associated processes and is needed for DIRC3 control of anchorage-independent growth. Our work indicates that lncRNA components of MITF-SOX10 networks are an important new class of melanoma regulators and candidate therapeutic targets that can act not only as downstream mediators of MITF-SOX10 function but as feedback regulators of MITF-SOX10 activity.

Comprehensive Analysis of lncRNAs Related to the Prognosis of Esophageal Cancer Based on ceRNA Network and Cox Regression Model

“…DIRC3 is upregulated in melanoma and may be used as an inhibitor of melanoma. But DIRC3 has not been shown to be significantly different in EC [ 43 ]. LINC00365 is upregulated in colorectal cancer specimens, and it may be involved in the process of CRC cells by mediating the Wnt/ β -catenin pathway [ 44 ].…”

Comprehensive Review on the Clinical Relevance of Long Non-Coding RNAs in Cutaneous Melanoma

“…Disrupted in Renal Carcinoma 3 ( DIRC3 ) lncRNA is, instead, a MITF-SOX10-regulated nuclear lncRNA, exerting its tumor-suppressor function by cis-acting and, in particular, by chromatin remodeling. It activates expression of its neighboring Insulin Like Growth Factor Binding Protein 5 ( IGFBP5 ) tumor suppressor gene, impacting the expression of its target genes [ 45 ].…”

Disease-Causing Mutations and Rearrangements in Long Non-coding RNA Gene Loci

“…The translocation results in a fusion of the DIRC3 lncRNA gene with the HSPBAP1 gene, with yet to be determined mechanistic consequences. In a screen for lncRNAs targeted by the melanoma transcription factors MITF and SOX10, DIRC3 was identified as a top hit and characterized as a melanoma tumor suppressor (Coe et al, 2019). Mechanistically, DIRC3 seems to promote expression of the tumor suppressor IGFBP5 through a chromatin loop, which brings both genes into close proximity.…”

“…Mechanistically, DIRC3 seems to promote expression of the tumor suppressor IGFBP5 through a chromatin loop, which brings both genes into close proximity. MITF and SOX10 suppress expression of DIRC3, which potentially contributes to melanoma development (Coe et al, 2019). Of note, MITF is co-gained with lncRNA SAMMSON (see section Amplifications and Deletions), suggesting several lncRNAs to act in a common cancer-associated circuitry.…”