Loss of the lipid transfer protein STARD7 triggers metabolic reprogramming and an epigenetic-mediated cell cycle arrest in breast cancer
Cancer cells have to constantly adapt their metabolism to support aberrant cell proliferation. However, the functional link between metabolic reprogramming and cell cycle progression remain largely unexplored. Mitochondria rely on the transfer of multiple lipids from the endoplasmic reticulum (ER) to their membranes to be functional. Several mitochondrial-derived metabolites influence cancer cell proliferation by modulating the epigenome. Here we show that the loss of STARD7, a lipid transfer protein whose expression is enhanced in breast cancer, leads to a profound metabolic reprogramming characterized by the increased synthesis of Carnitine derivatives and S-Adenosyl-L-methionine (SAM). Elevated SAM levels causes the accumulation of H3K27 trimethylation, a repressive mark, on many gene promoters coding for candidates involved in cell cycle progression and in the response to oxidative stress. As a result, STARD7 deficiency triggers cell cycle arrest, at least through defective ERa- and EGFR-dependent signaling pathways as well as to autophagy and ciliogenesis. Collectively, our data define STARD7 as a critical candidate involved in cell cycle progression in breast cancer. Overall design: RNAseq for 3 different conditions, one shCtrl and two different shSTAR7 KD derivatives. All conditions are in triplicates.