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MCL-1 is a Master Regulator of Cancer Dependency on Fatty Acid Oxidation

ABSTRACT: MCL-1 is an anti-apoptotic BCL-2 family protein essential for survival of diverse cell types and is a major driver of cancer and chemoresistance. The mechanistic basis for the oncogenic supremacy of MCL-1 among its anti-apoptotic homologs is unclear and implicates physiologic roles of MCL-1 beyond apoptotic suppression. Here we find that MCL-1-dependent hematologic cancer cells specifically rely on fatty acid oxidation (FAO) as a fuel source because of metabolic wiring enforced by MCL-1 itself. We demonstrate that FAO regulation by MCL-1 is independent of its anti-apoptotic activity, based on metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking an intact apoptotic pathway. Genetic deletion of Mcl-1 results in transcriptional downregulation of FAO pathway proteins such that glucose withdrawal triggers cell death despite apoptotic blockade. Our data reveal that MCL-1 is a master regulator of FAO, rendering MCL-1-driven cancer cells uniquely susceptible to treatment with FAO inhibitors.

ORGANISM(S): Mus musculus

PROVIDER: GSE196136 | GEO | 2022/10/04

REPOSITORIES: GEO

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MCL-1 Drives a Metabolic Dependency on Fatty Acid Oxidation in Cancer Independent of its Anti-Apoptotic Function

Project description:MCL-1 is an anti-apoptotic BCL-2 family protein essential to the survival of diverse cell types and is a major driver of cancer and chemoresistance. The unique oncogenic supremacy of MCL-1, as compared to its anti-apoptotic homologs, suggests that it has additional functions to complement apoptotic suppression. Here, we find that MCL-1-dependent hematologic cancer cells selectively rely on fatty acid oxidation (FAO) as a fuel source due to metabolic wiring enforced by MCL-1 itself. Importantly, this metabolic function is independent of anti-apoptotic activity, as demonstrated by metabolomic, proteomic, and genomic profiling of MCL-1-dependent leukemia cells lacking pro-apoptotic BAX and BAK. Genetic deletion of Mcl-1 results in selective downregulation of proteins within the FAO pathway, accompanied by cell death upon glucose deprivation despite apoptotic blockade. Our data reveal that MCL-1 drives a programmatic dependency on FAO in hematologic cancer cells, which can be effectively targeted by FAO inhibitors.

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