The Tumor-Promoting Role of TRIP4 in Melanoma Progression and its Involvement in Response to BRAF-Targeted Therapy

Abstract

TRIP4 was identified as having a proliferation promoting effect in melanoma cells based on small interfering RNA library screening, however, its precise function in melanoma progression is completely unknown. Here, we explored the carcinogenic role of TRIP4 in melanoma. The high expression of TRIP4 was observed in human melanoma cells and tissues. Its knockdown suppressed melanoma progression invitro and invivo, including melanoma cell proliferation, migration, and invasion inhibition and apoptosis induction. Further mechanistic analysis showed that TRIP4 promoted melanoma growth through modulation of COX-2 and iNOS expression partially by activating NF-κB signaling indirectly and partially by the direct anchoring of itself at COX-2 and iNOS promoter via synergy with p300. TRIP4 was confirmed to regulate the sensitivity to anti-BRAF targeted agents in BRAF-mutant human melanoma cells and xenografts. In addition, clinical data showed that high expression of TRIP4 was positively correlated with increased expression of COX-2 and iNOS and predicted poor prognosis in a cohort of 100 melanoma patients. Collectively, these results show a pro-tumorigenic role of TRIP4, provide an insight into the mechanism of TRIP4 as a candidate therapeutic target, and suggest the potential of TRIP4 and BRAF dual targeting as an effective therapeutic strategy for melanoma.