Characterisation of TRIM16 as a putative tumour suppressor protein and drug target in melanoma

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Embargoed until 2016-08-31
Copyright: Sutton, Selina
The incidence of cutaneous malignant melanoma is rapidly increasing. Melanoma is an extremely aggressive malignancy making up only 4% of total skin cancers, but it is responsible for 80% of skin cancer deaths. The clinical benefit of BRAF-MEK-inhibitor therapy in BRAF mutant melanoma remains temporary, and the mechanisms of metastasis with advanced disease are incompletely understood. The tripartite motif (TRIM) family members have been implicated in the pathogenesis of multiple cancers functioning as both oncogenes and tumour suppressors. Intriguingly, in the histological progression of squamous cell carcinoma (SCC) from normal skin, TRlM16 was significantly reduced in vivo and overexpression of TRlM16 reduced SCC cell migration in vitro. Furthermore, TRlM16 has demonstrated some of the features of a tumour suppressor protein in neuroblastoma through down-regulation of protein binding partners: cytoplasmic vimentin and nuclear E2F1. Taken together, these data suggest that TRIM16 acts to repress cancer cell replication and migration. However, the role of TRIM16 in melanoma is presently unknown. We developed a keratinocyte-specific TRlM16 knockout mouse model for the evaluation of TRIM16 in the development of SCC. Surprisingly, these mice demonstrated large cutaneous melanocytic lesions, indicating a possible role in melanoma. We then used human melanoma cell lines and primary tissues to show that low TRIM16 expression associates with enhanced cell migration in vitro, metastatic disease in vivo, and poor prognosis in a large cohort of melanoma patients with lymph node metastasis. TRIM16 protein expression is increased with vemurafenib BRAF inhibitor treatment in vitro and is partially required for drug mechanism of action. ln addition, TRlM16 protein expression is increased by BRAF inhibitor treatment in vivo. Taken together, these data indicated that repression of TRIM16 expression enhanced replication and migration of melanoma cells, associated with poor prognosis and thus represents as a potential therapeutic target. Furthermore, we identified a novel small molecule, compound 012, which unexpectedly increased BRAF inhibitor potency in BRAF wild-type mutant melanoma cells, an effect partially dependent on TRIM16. This establishes a basis for investigation of the combination of efficacious small molecules synergistic with vemurafenib, and may open an important novel treatment option for BRAF wild-type patients.
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Sutton, Selina
Cheung, Belamy
Marshall, Glenn
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PhD Doctorate
UNSW Faculty
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