Fatty Acid Oxidation is a Druggable Gateway Regulating Cellular Plasticity for Driving Metastasis in Breast Cancer

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2021 Oct 6

PMID 34613780

Citations 34

Authors

Ser Yue Loo

Li Ping Toh

William Haowei Xie

Elina Pathak

Wilson Tan

Siming Ma

May Yin Lee

S Shatishwaran

Joanna Zhen Zhen Yeo

Ju Yuan

Yin Ying Ho

Esther Kai Lay Peh

Magendran Muniandy

Federico Torta

Jack Chan

Tira J Tan

Yirong Sim

Veronique Tan

Benita Tan

Preetha Madhukumar

Wei Sean Yong

Kong Wee Ong

Chow Yin Wong

Puay Hoon Tan

Yoon Sim Yap

Lih-Wen Deng

Rebecca Dent

Roger Foo

Markus R Wenk

Soo Chin Lee

Ying Swan Ho

Elaine Hsuen Lim

Wai Leong Tam

Affiliations

Soon will be listed here.

Abstract

Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states.

Citing Articles

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