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 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.

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

“…14 By contrast, our data support PRE2 acting as a powerful enhancer element with the deletion allele increasing expression of IGFBP5 over and above that of the insertion allele with or without estradiol stimulation. Overall, our data are consistent with a hypothetical model in which the juxtaposition of the two ERa, FOXA1, GATA3 binding sites at PRE2 by deletion of approximately 1.4 kb of intervening sequence generates a single extended binding region (Figure 5B) that is causally associated with increased enhancer activity, higher levels of expression of the putative tumor suppressor gene IGFBP5, 42 and a reduction in breast cancer risk (OR ¼ 0.77, p ¼ 2.2 3 10 À29 ) that is largely restricted to ER þ disease.…”

The pleiotropic roles of circular and long noncoding RNAs in cutaneous melanoma

“…DIRC3 was described as a nuclear regulatory lncRNA that activated the expression of the neighboring IGFBP5 tumor suppressor gene. DIRC3 loss-of-function in three BRAF-mutant CM cell lines led to increased anchorage-independent growth, and SOX10 occupancy at putative regulatory elements within the DIRC3 locus [100]. Furthermore, DIRC3 depletion enhanced SOX10 mediated repression of IGFBP5 [100], which negatively regulated MAPK kinase signaling to inhibit BRAF-mutant A375 cell proliferation and metastasis [101].…”