Bi-allelic loss of CDKN2A initiates melanoma invasion via RB-BRN2 axis

International Conference on Cancer Biology & Drug Delivery

September 18-19, 2017 | Philadelphia, USA

Robert Judson

University of California, USA

Posters & Accepted Abstracts: J Cancer Sci Ther

Abstract :

CDKN2A acts as a critical tumor suppressor in melanoma, as evidenced by frequent loss of function mutations and deletions. Loss of CDKN2A is believed to permit escape from senescent pre-neoplastic cell populations through relief of a cell cycle block mediated by its two gene products. We performed a comprehensive analysis of CDKN2A gene status and mRNA and protein expression levels of CDKN2A gene products in a cohort of melanomas and their adjacent pre-neoplastic lesions. We observed that bi-allelic CDKN2A loss coincides with the progression stage when primary melanomas become invasive. In melanoma lines, p16INK4A, one of the protein products of the CDKN2A locus, is a potent barrier to metastasis, independent of its known role inhibiting cell proliferation. We genetically engineered primary human melanocytes to harbor CDKN2A deletions and/or BRAF V600E mutation at their endogenous BRAF locus. Using this physiologic model for the early phases of neoplastic transformation, we found no evidence for BRAF-induced senescence, rather observing that p16INK4A loss activates a master regulator of melanoma invasion, BRN2, through phospho-state specific binding of Rb to MITF. These results demonstrate that one of the most frequently altered genes across human cancers, CDKN2A, has an unexpected role in inhibiting cellular invasion through direct binding to lineage specific transcription factors and acts as an essential gatekeeper of early metastatic dissemination.