The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor.,PLOS Genetics

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The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor.
PLOS Genetics ( IF 4.0 ) Pub Date : 2019-12-27 , DOI: 10.1371/journal.pgen.1008501
Elizabeth A Coe ₁ , Jennifer Y Tan ₂ , Michael Shapiro ₁ , Pakavarin Louphrasitthiphol ₃ , Andrew R Bassett ₄ , Ana C Marques ₂ , Colin R Goding ₃ , Keith W Vance ₁

Affiliation

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.

中文翻译：

MITF-SOX10 调节的长非编码 RNA DIRC3 是一种黑色素瘤肿瘤抑制因子。

MITF 和 SOX10 转录因子调节对黑色素瘤增殖、侵袭和转移重要的基因的表达。尽管越来越多的证据表明长非编码 RNA (lncRNA) 在癌症（包括黑色素瘤）中的作用，但它们在 MITF-SOX10 转录程序中的功能仍然缺乏研究。在这里，我们鉴定了 245 个候选黑色素瘤相关 lncRNA，其位点由 MITF-SOX10 共同占据，并且在活性增强子样区域富集。我们的工作表明，其中一个肾癌中断 3 (DIRC3) 可能是临床上重要的 MITF-SOX10 调节的肿瘤抑制因子。人类黑色素瘤细胞中 DIRC3 的缺失导致锚定非依赖性生长增加，这是恶性转化的标志，而 DIRC3 表达低的黑色素瘤患者的生存率降低。DIRC3 是一种核 lncRNA，通过调节染色质结构和抑制 SOX10 与 DIRC3 基因座内假定的调控元件结合来激活其邻近 IGFBP5 肿瘤抑制因子的表达。反过来，IGFBP5 的 DIRC3 依赖性调节会影响癌症相关过程中涉及的基因表达，并且是 DIRC3 控制锚定非依赖性生长所必需的。我们的工作表明，MITF-SOX10 网络的 lncRNA 成分是一类重要的新型黑色素瘤调节剂和候选治疗靶点，不仅可以充当 MITF-SOX10 功能的下游介质，还可以充当 MITF-SOX10 活性的反馈调节剂。

更新日期：2019-12-29

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