Abstract
Tumor cells reprogram their metabolism to survive and grow in a challenging microenvironment. Some of this reprogramming is performed by epigenetic mechanisms. Epigenetics is in turn affected by metabolism; chromatin modifying enzymes are dependent on substrates that are also key metabolic intermediates. We have shown that the chromatin remodeling enzyme Brahma-related gene 1 (BRG1), an epigenetic regulator, is necessary for rapid breast cancer cell proliferation. The mechanism for this requirement is the BRG1-dependent transcription of key lipogenic enzymes and regulators. Reduction in lipid synthesis lowers proliferation rates, which can be restored by palmitate supplementation. This work has established BRG1 as an attractive target for breast cancer therapy. Unlike genetic alterations, epigenetic mechanisms are reversible, promising gentler therapies without permanent off-target effects at distant sites.
Highlights
Reviewed by: Feng Gong, University of Miami, USA Pilar Ramos, St
We have shown that the chromatin remodeling enzyme Brahma-related gene 1 (BRG1), an epigenetic regulator, is necessary for rapid breast cancer cell proliferation
MTORC1 increases the transcription of lipogenic genes, including key enzymes in fatty acid synthesis, such as acetyl CoA carboxylase (ACC), ATP citrate lyase (ACLY), and fatty acid synthase (FASN)
Summary
Levels of circulating molecules that serve as feedstock for metabolic pathways change with diet. These include plasmafree fatty acids and amino acids that increase after a meal [7] or plasma ketone bodies and free fatty acids that increase after a prolonged fast [8, 9]. AMP-activated Kinase (AMPK) is a master regulator of metabolism that can sense cellular energy status and respond by switching on and off pathways to achieve energy homeostasis [16, 17]. MTORC2 activates the cell signaling Ser/Thr protein kinase AKT, promotes cellular survival, regulates cytoskeletal dynamics, and regulates growth via SGK1 phosphorylation. An altered interplay of all of these mechanisms participates in the progressive reprogramming of metabolism with tumor progression
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