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Article: CRAF methylation by PRMT6 regulates aerobic glycolysis driven hepatocarcinogenesis via ERK‐dependent PKM2 nuclear relocalization and activation

TitleCRAF methylation by PRMT6 regulates aerobic glycolysis driven hepatocarcinogenesis via ERK‐dependent PKM2 nuclear relocalization and activation
Authors
Keywordsarginine methylation
hepatocellular carcinoma
Warburg effect
PKM2
PRMT6
Issue Date2019
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
Hepatology, 2019, Epub How to Cite?
AbstractMost tumor cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and promote tumorigenicity and drug resistance. Intriguingly, the molecular mechanisms underlying this phenomenon are not well understood. In this work, using gain‐ and loss‐of‐function in vitro studies in patient‐derived organoid and cell cultures as well as in vivo PET‐MRI animal models, we showed that PRMT6 regulates aerobic glycolysis in human hepatocellular carcinoma (HCC) through nuclear relocalization of pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. We found PRMT6 to methylate CRAF at arginine 100, interfere with its RAS/RAF binding potential and as a result alter ERK‐mediated PKM2 translocation into the nucleus. This altered PRMT6–ERK–PKM2 signaling axis was further confirmed in both a HCC mouse model with endogenous knockout of PRMT6 as well as in HCC clinical samples. We also identified PRMT6 as a novel target of hypoxia via the transcriptional repressor REST, linking PRMT6 with hypoxia in driving glycolytic events. Finally, we showed as a proof‐of‐concept the therapeutic potential of using 2‐deoxyglucose (2DG), a glycolysis inhibitor, to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC. Conclusion: Our findings indicate that the PRMT6‐ERK‐PKM2 regulatory axis is an important determinant of the Warburg effect in tumor cells and provide a mechanistic link between tumorigenicity, sorafenib resistance and glucose metabolism.
Persistent Identifierhttp://hdl.handle.net/10722/279432
ISSN
2019 Impact Factor: 14.679
2015 SCImago Journal Rankings: 4.752

 

DC FieldValueLanguage
dc.contributor.authorWong, TL-
dc.contributor.authorNg, KY-
dc.contributor.authorTan, KV-
dc.contributor.authorChan, LH-
dc.contributor.authorZhou, L-
dc.contributor.authorCHE, N-
dc.contributor.authorHoo, RLC-
dc.contributor.authorLee, TK-
dc.contributor.authorRichard, S-
dc.contributor.authorLo, CM-
dc.contributor.authorMan, K-
dc.contributor.authorKhong, PL-
dc.contributor.authorMa, S-
dc.date.accessioned2019-11-01T07:17:15Z-
dc.date.available2019-11-01T07:17:15Z-
dc.date.issued2019-
dc.identifier.citationHepatology, 2019, Epub-
dc.identifier.issn0270-9139-
dc.identifier.urihttp://hdl.handle.net/10722/279432-
dc.description.abstractMost tumor cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and promote tumorigenicity and drug resistance. Intriguingly, the molecular mechanisms underlying this phenomenon are not well understood. In this work, using gain‐ and loss‐of‐function in vitro studies in patient‐derived organoid and cell cultures as well as in vivo PET‐MRI animal models, we showed that PRMT6 regulates aerobic glycolysis in human hepatocellular carcinoma (HCC) through nuclear relocalization of pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. We found PRMT6 to methylate CRAF at arginine 100, interfere with its RAS/RAF binding potential and as a result alter ERK‐mediated PKM2 translocation into the nucleus. This altered PRMT6–ERK–PKM2 signaling axis was further confirmed in both a HCC mouse model with endogenous knockout of PRMT6 as well as in HCC clinical samples. We also identified PRMT6 as a novel target of hypoxia via the transcriptional repressor REST, linking PRMT6 with hypoxia in driving glycolytic events. Finally, we showed as a proof‐of‐concept the therapeutic potential of using 2‐deoxyglucose (2DG), a glycolysis inhibitor, to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC. Conclusion: Our findings indicate that the PRMT6‐ERK‐PKM2 regulatory axis is an important determinant of the Warburg effect in tumor cells and provide a mechanistic link between tumorigenicity, sorafenib resistance and glucose metabolism.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/-
dc.relation.ispartofHepatology-
dc.rightsPreprint This is the pre-peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Postprint This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.-
dc.subjectarginine methylation-
dc.subjecthepatocellular carcinoma-
dc.subjectWarburg effect-
dc.subjectPKM2-
dc.subjectPRMT6-
dc.titleCRAF methylation by PRMT6 regulates aerobic glycolysis driven hepatocarcinogenesis via ERK‐dependent PKM2 nuclear relocalization and activation-
dc.typeArticle-
dc.identifier.emailWong, TL: tinlwong@hku.hk-
dc.identifier.emailNg, KY: jkyng@hku.hk-
dc.identifier.emailTan, KV: kvtan@hku.hk-
dc.identifier.emailZhou, L: lenazhou@connect.hku.hk-
dc.identifier.emailHoo, RLC: rubyhoo@hkucc.hku.hk-
dc.identifier.emailLo, CM: chungmlo@hkucc.hku.hk-
dc.identifier.emailMan, K: kwanman@hku.hk-
dc.identifier.emailKhong, PL: plkhong@hku.hk-
dc.identifier.emailMa, S: stefma@hku.hk-
dc.identifier.authorityHoo, RLC=rp01334-
dc.identifier.authorityLo, CM=rp00412-
dc.identifier.authorityMan, K=rp00417-
dc.identifier.authorityKhong, PL=rp00467-
dc.identifier.authorityMa, S=rp00506-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/hep.30923-
dc.identifier.scopuseid_2-s2.0-85078660749-
dc.identifier.hkuros308361-
dc.publisher.placeUnited States-

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