Investigation of control of pRB and cell transformation by a long non-coding RNA

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Melanoma is a cancer of pigment producing cells called melanocytes, most often in the skin. Melanoma is the 6th most common cancer in the UK and advanced melanoma still has a very poor prognosis (www.cancerresearchuk.org). In 2016, approximately 13,300 people in the UK will be diagnosed with melanoma. At current rates, approximately 2,100 of these will die from the disease. Thus, there is a need for a better understanding of this disease to ultimately facilitate better cures. Remarkably, most people carry the earliest detectable skin lesions as precursors to melanoma, in the form of benign human nevi or moles. Moles typically carry one of the genetic alterations known to drive melanoma, either an activated NRAS or BRAF oncogene. However, moles only very rarely progress to melanoma because the melanocytes harboring the oncogene are prevented from proliferating by a process called cell senescence. Consequently, a better understanding of senescence in melanocytes can aid in understanding the body's natural defences to melanoma. Eventually, this might be harnessed in therapies. One molecule critical for cell senescence and preventing tumor formation is the retinoblastoma tumor suppressor (pRB). As its names suggests, this molecule was first discovered through its ability to prevent retinoblastoma, a cancer of the eye. However, pRB also contributes to suppression of melanoma and many other cancers, in part through activation of cell senescence. Thus, it is important to understand control of pRB. We have discovered another molecule, called LNC98, which is required for cells to produce pRB. This in turn suggests that LNC98 might suppress melanoma formation. Consistent with this idea, we have found that LNC98 is inactivated in some human melanomas, perhaps accounting for their unrestrained growth and proliferation. In this study, we will investigate the molecular mechanism by which LNC98 promotes production of pRB in cells and investigate the role of LNC98 in suppression of melanoma. Completion of these studies should provide new therapeutic avenues to manage and treat melanoma.