Long noncoding RNA DIO3OS induces glycolytic-dominant metabolic reprogramming to promote aromatase inhibitor resistance in breast cancer

Xueman Chen, Rong Luo, Yunmei Zhang, Shuying Ye, Xin Zeng, Jiang Liu, Di Huang, Yujie Liu, Qiang Liu, Man-Li Luo () and Erwei Song ()
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Xueman Chen: Sun Yat-Sen University
Rong Luo: Sun Yat-Sen University
Yunmei Zhang: Sun Yat-Sen University
Shuying Ye: Sun Yat-Sen University
Xin Zeng: Sun Yat-Sen University
Jiang Liu: Sun Yat-Sen University
Di Huang: Sun Yat-Sen University
Yujie Liu: Sun Yat-Sen University
Qiang Liu: Sun Yat-Sen University
Man-Li Luo: Sun Yat-Sen University
Erwei Song: Sun Yat-Sen University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Aromatase inhibition is an efficient endocrine therapy to block ectopic estrogen production for postmenopausal estrogen receptor (ER)-positive breast cancer patients, but many develop resistance. Here, we show that aromatase inhibitor (AI)-resistant breast tumors display features of enhanced aerobic glycolysis with upregulation of long noncoding RNA (lncRNA) DIO3OS, which correlates with poor prognosis of breast cancer patients on AI therapies. Long-term estrogen deprivation induces DIO3OS expression in ER-positive breast tumor cells, which further enhances aerobic glycolysis and promotes estrogen-independent cell proliferation in vitro and in vivo. Mechanistically, DIO3OS interacts with polypyrimidine tract binding protein 1 (PTBP1) and stabilizes the mRNA of lactate dehydrogenase A (LDHA) by protecting the integrity of its 3’UTR, and subsequently upregulates LDHA expression and activates glycolytic metabolism in AI-resistant breast cancer cells. Our findings highlight the role of lncRNA in regulating the key enzyme of glycolytic metabolism in response to endocrine therapies and the potential of targeting DIO3OS to reverse AI resistance in ER-positive breast cancer.

Date: 2022
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DOI: 10.1038/s41467-022-34702-x

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