Expression of the cholesterol transporter SR-B1 in melanoma cells facilitates inflammatory signaling leading to reduced cholesterol synthesis

Scavenger receptor class B type 1 (SR-B1) is a cholesterol transporter, abundantly expressed in human melanoma, yet its precise role for melanoma progression is not fully understood. This study investigates the involvement of SR-B1 in cholesterol homeostasis of tumor cells and its implications for potential therapy. We found that SR-B1 depletion in melanoma cells does not alter total cholesterol levels, but induces cholesterol biosynthesis. This effect was characterized by an increased expression of HMG-CoA reductase (HMGCR), a rate limiting enzyme of cholesterol biosynthesis. Notably, further analyses indicated that this regulation occurs at the post-translational level, mediated via the hypoxia-inducible factor (HIF) signaling pathway. Importantly, we identified SR-B1 as a transporter of the lipid hormone sphingosine-1-phosphate (S1P) and we found that S1P exposure leads to HIF1A up-regulation. Finally, we used a pluripotent stem cell-derived skin organoid model to show that targeting SR-B1 in combination with targeted melanoma therapy can lead to increased apoptosis and suppressed proliferation of transplanted tumor cells. Our study shows that functional SR-B1 is linked to inflammatory signaling, which reduces cholesterol synthesis, while enabling melanoma cell survival during chemotherapy treatment.