Abstract
Long non-coding RNAs (lncRNAs), that are not translated into protein, comprise a large proportion of transcripts produced by the eukaryotic genome. While many lncRNAs have now been identified, functional characterisation of these transcripts is still limited. However, as more lncRNAs are being studied, they are being recognised as important regulators of key cellular and developmental programmes. With that, dysregulated activity of lncRNAs is also now connected to numerous types of disease, including cancers.Melanoma is a particularly aggressive form of skin cancer which is associated with a high death rate. With currently limited effective therapeutic options, lncRNAs may represent a new class of therapeutic targets. Two well-characterised proteins in melanocyte and melanoma development are MITF and SOX10. These transcription factors regulate the expression of genes important for melanoma cell proliferation, invasion, and metastasis. While protein-coding genes within the MITF-SOX10 transcriptional programmes are well studied, lncRNAs are not. By understanding the role of lncRNAs in such processes, our knowledge of melanoma development and progression can be enhanced, and possible methods of treatment may be revealed.
For this study, a group of 12 candidate MITF-regulated lncRNAs expressed in melanocytes and/or melanoma cells were initially selected. The nuclear-expressed intergenic lncRNA Disrupted In Renal Carcinoma (DIRC3) was prioritised for further investigation, as a representative lncRNA involved in the MITF-SOX10 transcriptional response in melanoma. Melanoma patients classified as expressing low levels of DIRC3 were found to have decreased survival. Knockdown analysis then led to the identification of DIRC3 as a MITF-SOX10 regulated tumour suppressor in melanoma that inhibits anchorage-independent growth. DIRC3 appears to perform this function by activating expression of its neighbouring tumour suppressive gene IGFBP5. DIRC3 regulates IGFBP5 expression through modulating the chromatin structure across its own locus so that it suppresses the ability of SOX10 to bind to putative regulatory elements. Such regulation of IGFPB5 also goes on to impact expression of numerous genes involved in cancer-associated processes.
This project highlights the role of DIRC3 as a tumour suppressive lncRNA in melanoma. Through participating in the regulation of the MITF-SOX10 transcriptional programme, DIRC3 inhibits anchorage-independent growth, a key hallmark of malignant transformation. This activity demonstrates the potential important roles lncRNAs may play within such regulatory networks as well as implicate them as candidate biomarkers or therapeutic targets.
| Date of Award | 1 Apr 2020 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Keith Vance (Supervisor) & Adele Murrell (Supervisor) |