Transcriptional co-activator regulates melanocyte differentiation and oncogenesis by integrating cAMP and MAPK/ERK pathways

The cyclic AMP pathway promotes melanocyte differentiation in part by triggering gene expression changes mediated by CREB and its coactivators (CRTC1-3). Differentiation is dysregulated in melanomas, although the contributions of different cAMP effectors in this setting is unclear. We report a selective differentiation impairment in CRTC3 KO melanocytes and melanoma cells, due to downregulation of OCA2 and block of melanosome maturation. CRTC3 stimulated OCA2 expression via binding to CREB on a conserved enhancer, a regulatory site for pigmentation and melanoma risk in humans. Response to cellular signaling differed between CRTC3 and its family members; CRTC3 was uniquely activated by ERK1/2-mediated phosphorylation at Ser391 and by low levels of cAMP. Phosphorylation at Ser391 was constitutively elevated in human melanoma cells with hyperactivated ERK1/2 signaling; knockout of CRTC3 in this setting impaired anchorage-independent growth, migration and invasiveness while CRTC3 overexpression supported cell survival in response to MAPK inhibition by vemurafenib. Human melanomas expressing gain of function mutations in CRTC3 were associated with poorer clinical outcome. Our results suggest that CRTC3 inhibition may provide benefit in the treatment of hyperpigmentation and melanoma, and potentially other disorders with deregulated cAMP/MAPK crosstalk.