PT  - JOURNAL ARTICLE
AU  - Elizabeth A Coe
AU  - Jennifer Y Tan
AU  - Michael Shapiro
AU  - Pakavarin Louphrasitthiphol
AU  - Andrew R Bassett
AU  - Ana C Marques
AU  - Colin R Goding
AU  - Keith W Vance
TI  - The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor
AID  - 10.1101/591065
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 591065
4099  - http://biorxiv.org/content/early/2019/03/27/591065.short
4100  - http://biorxiv.org/content/early/2019/03/27/591065.full
AB  - 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 identified 245 candidate melanoma associated lncRNAs whose loci are co-occupied by MITF-SOX10 and that are enriched at active enhancer-like regions. We characterise the function and molecular mechanism of action of one of these lncRNAs, Disrupted In Renal Carcinoma 3 (DIRC3), and show that it operates as a 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 functions locally to activate 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 multiple cancer associated processes. Our work indicates that lncRNA components of the MITF-SOX10 networks are an important new class of melanoma regulators and candidate therapeutic targets.