The lipid droplet protein DHRS3 is a regulator of melanoma cell state

Lipid droplets are fat storage organelles composed of a protein envelope and a lipid rich core. Dynamic regulation of this protein envelope underlies differential lipid droplet formation and function in diverse cell types. In melanoma, the ability to form lipid droplets has been linked to tumor progression and metastasis, but it is not known whether lipid droplet proteins play a role in these phenotypes. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that proteins expressed in the lipid droplet were differentially enriched in distinct melanoma states, ranging from melanocytic to neural crest like. DHRS3, which is involved in the conversion of all-trans-retinal to all-trans-retinol, is significantly upregulated in the MITFLO/neural crest-like melanoma cell state, and markedly reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive the MITFHI/melanocytic cells to a more undifferentiated and invasive state. These changes are due to retinoic acid mediated regulation of melanocytic genes through the retinoid X receptors (RXR). Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling.