Stearoyl-CoA Desaturase-1 Drives Tumor Growth by Interacting With Histone Deacetylase-2 and Deacetylating Nucleophosmin-1.

The adaptation of lipid metabolism in cancer cells, driven by changes in the tumor microenvironment, presents major challenges for cancer therapy. Here, we addressed the problem of altered lipid metabolism and its role in cancer progression and therapeutic resistance. We demonstrate that hypoxia upregulates the key desaturase, stearoyl-CoA desaturase-1 (SCD1), and the lipid droplet (LD) protein PLIN2, thus promoting lipid metabolic adaptation, cell proliferation, migration, and tumor growth. We found that SCD1 and PLIN2 are essential and interdependent for LD formation. PLIN2 supports cell survival under hypoxic and metabolic stress, whereas SCD1 sustains cancer cell proliferation upon reoxygenation. In addition, we found that SCD1 expression in cancer cells affects nonhistone protein deacetylation, whereas PLIN2 expression enhances protein acetylation. Among these proteins, nucleophosmin(NPM1), a tumor suppressor and regulator of p53, was destabilized through SCD1-dependent deacetylation. In addition, SCD1 interacts with NPM1, influences its cellular localization, and recruits histone deacetylase-2 (HDAC2) to the complex. Notably, we observed that knockdown of SCD1 in vitro or its pharmacological inhibition in vivo enhances cancer cell sensitivity to HDAC inhibitors. Our findings underscore the role of SCD1 in reshaping the cellular acetylome and suggest that targeting SCD1 could sensitize cancer cells to HDAC inhibitors, highlighting a promising therapeutic strategy.