Suppression of miR-199a maturation by HuR is crucial for hypoxia-induced glycolytic switch in hepatocellular carcinoma

The EMBO Journal
Ling-Fei ZhangMo-Fang Liu

Abstract

Glucose metabolic reprogramming is a hallmark of cancer. Cancer cells rapidly adjust their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate in a hypoxic environment, but the mechanism underlying this switch is still incompletely understood. Here, we report that hypoxia potently induces the RNA-binding protein HuR to specifically bind primary miR-199a transcript to block miR-199a maturation in hepatocellular carcinoma (HCC) cells. We demonstrate that this hypoxia-suppressed miR-199a plays a decisive role in limiting glycolysis in HCC cells by targeting hexokinase-2 (Hk2) and pyruvate kinase-M2 (Pkm2). Furthermore, systemically delivered cholesterol-modified agomiR-199a inhibits [(18)F]-fluorodeoxyglucose uptake and attenuates tumor growth in HCC tumor-bearing mice. These data reveal a novel mechanism of reprogramming of cancer energy metabolism in which HuR suppresses miR-199a maturation to link hypoxia to the Warburg effect and suggest a promising therapeutic strategy that targets miR-199a to interrupt cancerous aerobic glycolysis.

References

Feb 24, 1956·Science·O WARBURG
Apr 5, 2005·Nature Genetics·Azra KrekNikolaus Rajewsky
Jan 27, 2007·Blood·Karin FischerMarina Kreutz
Apr 7, 2007·Cancer Metastasis Reviews·Pawel SwietachAdrian L Harris
Jun 19, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·David A MankoffKenneth A Krohn
Oct 31, 2007·Molecular and Cellular Biology·Stefanie GalbánMyriam Gorospe
Dec 14, 2007·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Jeffrey R TsengSanjiv S Gambhir
Jan 22, 2008·Molecular Cell·Ligang Wu, Joel G Belasco
Feb 23, 2008·Science·Srinivas R ViswanathanRichard I Gregory
Apr 3, 2008·Annals of Medicine·Douglas J Guarnieri, Ralph J DiLeone
Jun 10, 2008·Cancer Cell·Guido Kroemer, Jacques Pouyssegur
Jun 27, 2008·Cellular and Molecular Life Sciences : CMLS·M N Hinman, H Lou
Nov 26, 2008·Nucleic Acids Research·Youn-Bok LeeJames B Uney
Apr 29, 2009·Molecular and Cellular Biology·Shuji SakamotoYasutoshi Agata
May 23, 2009·Science·Matthew G Vander HeidenCraig B Thompson
Jun 30, 2009·Nature Biotechnology·Debashish RayTimothy R Hughes
Jul 9, 2009·Journal of Cellular and Molecular Medicine·Kiyoshi MasudaMyriam Gorospe
Sep 29, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Samantha YeligarVijay K Kalra
Nov 28, 2009·Current Opinion in Genetics & Development·Gregg L Semenza
Jun 24, 2010·Cancer Research·Jason F WigginsAndreas G Bader
Oct 5, 2010·Nature Reviews. Drug Discovery·Ramiro GarzonCarlo M Croce
Oct 23, 2010·Molecular Cell·Amar J MajmundarM Celeste Simon
May 25, 2011·Nature Reviews. Cancer·William R Wilson, Michael P Hay
Sep 1, 2011·Nature Reviews. Drug Discovery·Matthew G Vander Heiden
Oct 14, 2011·The New England Journal of Medicine·Hashem B El-Serag
Oct 27, 2011·Cancer Biology & Therapy·Imran A BabarFrank J Slack
Jul 25, 2012·Trends in Endocrinology and Metabolism : TEM·Weibo Luo, Gregg L Semenza
Jan 12, 2013·Genes & Development·Nila Roy ChoudhuryGracjan Michlewski
Jan 19, 2013·Developmental Cell·Shuang ZhaoMo-Fang Liu
Jun 9, 2015·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Weijie GuoXianghuo He

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Citations

Nov 7, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Aditi VarshneyVirander S Chauhan
Oct 20, 2018·RNA·Gracjan Michlewski, Javier F Cáceres
Jan 11, 2018·Nature Reviews. Gastroenterology & Hepatology·Chun-Ming WongIrene Oi-Lin Ng
Jan 8, 2020·Antioxidants & Redox Signaling·Pau B Esparza-Moltó, José M Cuezva
May 12, 2017·Oncotarget·Chu Chen, Tao Lou
Oct 16, 2016·American Journal of Physiology. Heart and Circulatory Physiology·Mark V PintiJohn M Hollander
May 5, 2017·Frontiers in Cellular and Infection Microbiology·Mingna ZhaoJiatao Lou
Aug 10, 2017·The Journal of Biological Chemistry·Natalia FilippovaL Burt Nabors
Sep 17, 2020·International Journal of Molecular Sciences·Dobrochna DolickaMichelangelo Foti
Mar 21, 2020·Frontiers in Oncology·Kulsoom ZahraUma Pandey
Feb 28, 2016·British Journal of Pharmacology·P Urbánek, L-O Klotz
Jul 8, 2020·Journal of Experimental & Clinical Cancer Research : CR·Jiao FengChuanyong Guo
May 21, 2021·Journal of Hepatocellular Carcinoma·Laura GramantieriFrancesca Fornari
Sep 15, 2021·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Pallavi SubramanianTriantafyllos Chavakis

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