MCL-1 Drives Programmatic Dependency on Fatty Acid Oxidation in Cancer

Abstract

BCL-2 family proteins regulate the critical balance between cellular life and death through control of the mitochondrial apoptotic pathway. MCL-1 is a distinctive anti-apoptotic BCL-2 family protein that is required in early development as well as in the homeostatic maintenance of various cell types and tissues. Furthermore, MCL-1 has emerged as one of the most potent pathogenic factors in the development and chemoresistance of human cancer. Recently documented non-canonical roles of MCL-1 in metabolic regulation could help explain its key contributions to homeostasis and disease. Given that certain cancer cells can undergo advantageous bioenergetic alterations, we set out to investigate a link between MCL-1 and metabolic regulation in cancer, with a particular focus on implications for cancer progression. Here, we establish that MCL-1 drives dependency on fatty acid oxidation (FAO) in cancer, a role independent from its ability to suppress programmed cell death. Loss of MCL-1 elicits a metabolic rewiring from a lipid- to glucose-utilizing state, which is accompanied by transcriptional downregulation of the global FAO program. MCL-1-mediated upregulation of FAO renders cells reliant on this metabolic pathway for survival, such that targeting FAO or a master regulator of lipid metabolism, peroxisome proliferator-activated receptor (PPAR), is selectively lethal. Collectively, these findings provide new insight into MCL-1’s oncogenic activity and identify a metabolic vulnerability that could be targeted for therapeutic benefit in cancer.