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


Autoři: Elizabeth A. Coe aff001;  Jennifer Y. Tan aff002;  Michael Shapiro aff001;  Pakavarin Louphrasitthiphol aff003;  Andrew R. Bassett aff004;  Ana C. Marques aff002;  Colin R. Goding aff003;  Keith W. Vance aff001
Působiště autorů: Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom aff001;  Department of Computational Biology, University of Lausanne, Lausanne, Switzerland aff002;  Ludwig Institute for Cancer Research, University of Oxford, Oxford, United Kingdom aff003;  Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom aff004
Vyšlo v časopise: The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008501
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008501

Souhrn

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.

Klíčová slova:

Gene expression – Gene regulation – Chromatin – Long non-coding RNAs – Melanoma cells – Melanomas – Transcriptional control – Tumor suppressor genes


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Štítky
Genetika Reprodukční medicína

Článek vyšel v časopise

PLOS Genetics


2019 Číslo 12

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