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Conference Paper: PRMT6-dependent CRAF/ERK signaling regulates cancer stem cell plasticity in liver cancer

TitlePRMT6-dependent CRAF/ERK signaling regulates cancer stem cell plasticity in liver cancer
Authors
Issue Date2017
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Proceedings of the 108th Annual Meeting of the American Association for Cancer Research (AACR 2017), Washington, DC, USA, 1-5 April 2017. In Cancer Research, 2017, v. 77 n. 13, Suppl., p. Abstract no. LB-139 How to Cite?
AbstractHepatocellular carcinoma (HCC), the major type of liver cancer, remains one of the most prevalent and deadliest cancer types in the world. Contemporary challenge in treating HCC has been the common therapy resistance and recurrence after therapy, all of which have been reported to be associated with stemlike behavior of cancer cells. Our group has previously identified a functional liver cancer stem cell (CSC) subset marked by the CD133 cell surface phenotype. Utilizing a PCR array encompassing diverse human chromatin modifiers, protein arginine methyltransferase 6 (PRMT6) was found to be differentially down regulated in CD133+ liver CSCs of human HCC cells as well as CD133 enriched chemoresistant hepatospheres as compared to their counterparts. Clinically, reduced PRMT6 expression was detected in HCC specimens and correlated with a higher risk of metastasis. PRMT6 negatively regulated diverse in vitro cancer stem cell properties of HCC cells including self-renewal, therapy resistance, metastasis and expression of CSC and pluripotency markers. In addition, PRMT6 also suppressed in vivo tumor initiation and serial transplantation. Surprising, contrary to its usual localization in the nucleus as a chromatin modification enzyme mediating histone H3R2 methylation, we found PRMT6 to be predominantly expressed in the cytoplasm in normal liver and HCC cells. Through tandem affinity purification and subsequent mass spectrometry profiling, we identified CRAF, a serine/threonine-protein kinase, as a novel cytoplasmic protein partner of PRMT6. Binding of PRMT6 to CRAF inhibited its kinase activity through site-specific arginine methylation, resulting in inhibition of ERK mediated CSC plasticity in HCC, demonstrated through in vivo / in vitro methylation assays, kinase assay and functional rescue experiments with the ERK inhibitor U0126. The link between PRMT6, ERK and cancer stemness was further substantiated in primary human normal liver and HCC organoids with or without PRMT6 modulated. Taken together, we found PRMT6 to be down-regulated in the liver CSC subset and to be functionally involved in regulating liver CSC plasticity via an unprecedented role in the cytoplasm through suppression of CRAF/ERK cascade.
Persistent Identifierhttp://hdl.handle.net/10722/246031
ISSN
2017 Impact Factor: 9.13
2015 SCImago Journal Rankings: 5.372
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChan, HL-
dc.contributor.authorZhou, L-
dc.contributor.authorNg, KY-
dc.contributor.authorWong, TL-
dc.contributor.authorChai, S-
dc.contributor.authorLee, TK-
dc.contributor.authorGuan, X-
dc.contributor.authorChing, YP-
dc.contributor.authorLo, CM-
dc.contributor.authorMan, K-
dc.contributor.authorArtegiani, B-
dc.contributor.authorClevers, H-
dc.contributor.authorYan, HHN-
dc.contributor.authorLeung, SY-
dc.contributor.authorRichard, S-
dc.contributor.authorHuen, MSY-
dc.contributor.authorMa, SKY-
dc.date.accessioned2017-09-18T02:21:10Z-
dc.date.available2017-09-18T02:21:10Z-
dc.date.issued2017-
dc.identifier.citationProceedings of the 108th Annual Meeting of the American Association for Cancer Research (AACR 2017), Washington, DC, USA, 1-5 April 2017. In Cancer Research, 2017, v. 77 n. 13, Suppl., p. Abstract no. LB-139-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/246031-
dc.description.abstractHepatocellular carcinoma (HCC), the major type of liver cancer, remains one of the most prevalent and deadliest cancer types in the world. Contemporary challenge in treating HCC has been the common therapy resistance and recurrence after therapy, all of which have been reported to be associated with stemlike behavior of cancer cells. Our group has previously identified a functional liver cancer stem cell (CSC) subset marked by the CD133 cell surface phenotype. Utilizing a PCR array encompassing diverse human chromatin modifiers, protein arginine methyltransferase 6 (PRMT6) was found to be differentially down regulated in CD133+ liver CSCs of human HCC cells as well as CD133 enriched chemoresistant hepatospheres as compared to their counterparts. Clinically, reduced PRMT6 expression was detected in HCC specimens and correlated with a higher risk of metastasis. PRMT6 negatively regulated diverse in vitro cancer stem cell properties of HCC cells including self-renewal, therapy resistance, metastasis and expression of CSC and pluripotency markers. In addition, PRMT6 also suppressed in vivo tumor initiation and serial transplantation. Surprising, contrary to its usual localization in the nucleus as a chromatin modification enzyme mediating histone H3R2 methylation, we found PRMT6 to be predominantly expressed in the cytoplasm in normal liver and HCC cells. Through tandem affinity purification and subsequent mass spectrometry profiling, we identified CRAF, a serine/threonine-protein kinase, as a novel cytoplasmic protein partner of PRMT6. Binding of PRMT6 to CRAF inhibited its kinase activity through site-specific arginine methylation, resulting in inhibition of ERK mediated CSC plasticity in HCC, demonstrated through in vivo / in vitro methylation assays, kinase assay and functional rescue experiments with the ERK inhibitor U0126. The link between PRMT6, ERK and cancer stemness was further substantiated in primary human normal liver and HCC organoids with or without PRMT6 modulated. Taken together, we found PRMT6 to be down-regulated in the liver CSC subset and to be functionally involved in regulating liver CSC plasticity via an unprecedented role in the cytoplasm through suppression of CRAF/ERK cascade.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.titlePRMT6-dependent CRAF/ERK signaling regulates cancer stem cell plasticity in liver cancer-
dc.typeConference_Paper-
dc.identifier.emailZhou, L: lenazhou@connect.hku.hk-
dc.identifier.emailNg, KY: jkyng@hku.hk-
dc.identifier.emailWong, TL: tinlwong@hku.hk-
dc.identifier.emailGuan, X: xyguan@hkucc.hku.hk-
dc.identifier.emailChing, YP: ypching@hku.hk-
dc.identifier.emailLo, CM: chungmlo@hkucc.hku.hk-
dc.identifier.emailMan, K: kwanman@hku.hk-
dc.identifier.emailYan, HHN: yanhelen@hkucc.hku.hk-
dc.identifier.emailLeung, SY: suetyi@hku.hk-
dc.identifier.emailHuen, MSY: huen.michael@hku.hk-
dc.identifier.emailMa, SKY: stefma@hku.hk-
dc.identifier.authorityGuan, X=rp00454-
dc.identifier.authorityChing, YP=rp00469-
dc.identifier.authorityLo, CM=rp00412-
dc.identifier.authorityMan, K=rp00417-
dc.identifier.authorityYan, HHN=rp01994-
dc.identifier.authorityLeung, SY=rp00359-
dc.identifier.authorityHuen, MSY=rp01336-
dc.identifier.authorityMa, SKY=rp00506-
dc.identifier.doi10.1158/1538-7445.AM2017-LB-139-
dc.identifier.hkuros278643-
dc.identifier.volume77-
dc.identifier.issue13, Suppl.-
dc.identifier.isiWOS:000442496700272-
dc.publisher.placeUnited States-

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