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| Status |
Public on Nov 11, 2019 |
| Title |
The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 non-coding RNAs (lncRNAs) in melanoma and other cancers, their functions within MITF-SOX10 transcriptional programmes is poorly investigated. Here, we identify 245 candidate melanoma associated lncRNAs whose loci are co-occupied by MITF-SOX10 and 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 modulation of chromatin structure and suppression of SOX10 binding to putative regulatory elements within the DIRC3 locus. In turn, DIRC3 dependent regulation of IGFBP5 impacts the expression of genes important for cell metabolism, oxidative phosphorylation and cancer. Our work indicates that lncRNA components of MITF-SOX10 networks are an important new class of melanoma regulators and candidate therapeutic targets.
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| Overall design |
2 melanoma and 1 melanocyte cell lines were subjected to
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| Contributor(s) |
Louphrasitthiphol P, Goding CR |
| Citation(s) |
31881017 |
| |
| Submission date |
Mar 29, 2019 |
| Last update date |
Jan 14, 2020 |
| Contact name |
Pakavarin Louphrasitthiphol |
| E-mail(s) |
pakavarin.louphrasitthiphol@ludwig.ox.ac.uk
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| Phone |
01865 617543
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| Organization name |
Ludwig Institute for Cancer Research
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| Department |
Nuffield Department of Clinical Medicine
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| Lab |
Prof. CRGoding
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| Street address |
Old Road Campus Research Building (off Roosevelt Drive)
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| City |
Oxford |
| ZIP/Postal code |
OX3 7DQ |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA529912 |
| SRA |
SRP189902 |
