DHCR24 Promotes Melanoma Stem-Like Cells Formation and Mediates Vemurafenib Resistance by Accumulating 27-Hydroxycholesterol

Abstract:Background: Melanoma is the most serious skin cancer with gradually increased incidence and poor prognosis mainly as the result of cancer stem cell (CSC) expansion and drug resistance. Some studies have suggested that dysregulated cholesterol homeostasis increasing tumorigenicity and metastasis in cancers. In the present study, our objective was to elucidate the contribution of 24-Dehydrocholesterol reductase (DHCR24) towards melanoma progression and drug resistance.Methods: Immunohistochemistry and HE staining were performed for determing the expression of DHCR24 in melanoma patients, lentivirus perturbation and functional assays were used to evaluate the ability of turmorigenesis of DHCR24 altered melanoma cells and melanoma stem-like cells. RNA sequencing (RNA-seq) and targeted metabolomics were carried out for identifying metabolites which contributes melanoma stem-like cell expansion and vemurafenib treatment resistance.Results: DHCR24 was over-expressed in melanoma patients while knockdown of DHCR24 blocked melanoma cells in S phase and lead to significant inhibition in proliferation and migration. Meanwhile, forced expression of DHCR24 promotes the growth of melanoma cells in xenograft mice. We further demonstrated that DHCR24 promotes the proliferation of melanoma stem-like cell populations by activating Rap1/AKT signaling and result in accumulation of cellular 27-Hydroxycholesterol (27-HC) contents. Next, we validated that both CYP27A1 and 27-HC administration contributed to melanoma stem-like cells formation and vemurafenib resistance through AKT-308/309 phosphorylation. Conclusions: Our data confirmed the oncogenic role of DHCR24 in melanoma stem-like cells proliferation and vemurafenib resistance by regulating 27-HC. These findings established the basis of targeting DHCR24 as a potential therapeutic target for advanced melanoma.