PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation

Lok Hei Chan; Lei Zhou; Kai Yu Ng; Tin Lok Wong; Terence K Lee; Rakesh Sharma; Jane H Loong; Yick Pang Ching; Yun-Fei Yuan; Dan Xie; Chung Mau Lo; Kwan Man; Benedetta Artegiani; Hans Clevers; Helen H Yan; Suet Yi Leung; Stéphane Richard; Xin-Yuan Guan; Michael S Y Huen; Stephanie Ma

doi:10.1016/j.celrep.2018.09.053

PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation

Lok Hei Chan, Lei Zhou, Kai Yu Ng, Tin Lok Wong, Terence K Lee, Rakesh Sharma, Jane H Loong, Yick Pang Ching, Yun-Fei Yuan, Dan Xie, Chung Mau Lo, Kwan Man, Benedetta Artegiani, Hans Clevers, Helen H Yan, Suet Yi Leung, Stéphane Richard, Xin-Yuan Guan, Michael S Y Huen, Stephanie Ma

Research output: Contribution to journal › Article › peer-review

71 Citations (Scopus)

Abstract

Arginine methylation is a post-translational modification that plays pivotal roles in signal transduction and gene transcription during cell fate determination. We found protein methyltransferase 6 (PRMT6) to be frequently downregulated in hepatocellular carcinoma (HCC) and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis, and therapy resistance potential of HCC cell lines and patient-derived organoids. Consistently, loss of PRMT6 expression aggravated liver tumorigenesis in a chemical-induced HCC PRMT6 knockout (PRMT6-/-) mouse model. Integrated transcriptome and protein-protein interaction studies revealed an enrichment of genes implicated in RAS signaling and showed that PRMT6 interacted with CRAF on arginine 100, which decreased its RAS binding potential and altered its downstream MEK/ERK signaling. Our work describes a critical repressive function for PRMT6 in maintenance of HCC cells by regulating RAS binding and MEK/ERK signaling via methylation of CRAF on arginine 100.

Original language	English
Pages (from-to)	690-701.e8
Journal	Cell reports
Volume	25
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2018.09.053
Publication status	Published - 16 Oct 2018
Externally published	Yes

Keywords

Animals
Apoptosis
Carcinoma, Hepatocellular/genetics
Cell Proliferation
DNA Methylation
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms/genetics
MAP Kinase Kinase 1/genetics
MAP Kinase Signaling System
Male
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, Knockout
Mice, Nude
Mice, SCID
Neoplastic Stem Cells/metabolism
Nuclear Proteins/genetics
Protein-Arginine N-Methyltransferases/genetics
TNF Receptor-Associated Factor 3/genetics
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
raf Kinases/genetics
ras Proteins/genetics

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10.1016/j.celrep.2018.09.053

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Chan, L. H., Zhou, L., Ng, K. Y., Wong, T. L., Lee, T. K., Sharma, R., Loong, J. H., Ching, Y. P., Yuan, Y-F., Xie, D., Lo, C. M., Man, K., Artegiani, B., Clevers, H., Yan, H. H., Leung, S. Y., Richard, S., Guan, X-Y., Huen, M. S. Y., & Ma, S. (2018). PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation. Cell reports, 25(3), 690-701.e8. https://doi.org/10.1016/j.celrep.2018.09.053

@article{d35f39574f9344e2bbba6dee5e88fdf5,

title = "PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation",

abstract = "Arginine methylation is a post-translational modification that plays pivotal roles in signal transduction and gene transcription during cell fate determination. We found protein methyltransferase 6 (PRMT6) to be frequently downregulated in hepatocellular carcinoma (HCC) and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis, and therapy resistance potential of HCC cell lines and patient-derived organoids. Consistently, loss of PRMT6 expression aggravated liver tumorigenesis in a chemical-induced HCC PRMT6 knockout (PRMT6-/-) mouse model. Integrated transcriptome and protein-protein interaction studies revealed an enrichment of genes implicated in RAS signaling and showed that PRMT6 interacted with CRAF on arginine 100, which decreased its RAS binding potential and altered its downstream MEK/ERK signaling. Our work describes a critical repressive function for PRMT6 in maintenance of HCC cells by regulating RAS binding and MEK/ERK signaling via methylation of CRAF on arginine 100.",

keywords = "Animals, Apoptosis, Carcinoma, Hepatocellular/genetics, Cell Proliferation, DNA Methylation, Gene Expression Regulation, Neoplastic, Humans, Liver Neoplasms/genetics, MAP Kinase Kinase 1/genetics, MAP Kinase Signaling System, Male, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Mice, Knockout, Mice, Nude, Mice, SCID, Neoplastic Stem Cells/metabolism, Nuclear Proteins/genetics, Protein-Arginine N-Methyltransferases/genetics, TNF Receptor-Associated Factor 3/genetics, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, raf Kinases/genetics, ras Proteins/genetics",

author = "Chan, {Lok Hei} and Lei Zhou and Ng, {Kai Yu} and Wong, {Tin Lok} and Lee, {Terence K} and Rakesh Sharma and Loong, {Jane H} and Ching, {Yick Pang} and Yun-Fei Yuan and Dan Xie and Lo, {Chung Mau} and Kwan Man and Benedetta Artegiani and Hans Clevers and Yan, {Helen H} and Leung, {Suet Yi} and St{\'e}phane Richard and Xin-Yuan Guan and Huen, {Michael S Y} and Stephanie Ma",

year = "2018",

month = oct,

day = "16",

doi = "10.1016/j.celrep.2018.09.053",

language = "English",

volume = "25",

pages = "690--701.e8",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

}

Chan, LH, Zhou, L, Ng, KY, Wong, TL, Lee, TK, Sharma, R, Loong, JH, Ching, YP, Yuan, Y-F, Xie, D, Lo, CM, Man, K, Artegiani, B , Clevers, H, Yan, HH, Leung, SY, Richard, S, Guan, X-Y, Huen, MSY & Ma, S 2018, 'PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation', Cell reports, vol. 25, no. 3, pp. 690-701.e8. https://doi.org/10.1016/j.celrep.2018.09.053

TY - JOUR

T1 - PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation

AU - Chan, Lok Hei

AU - Zhou, Lei

AU - Ng, Kai Yu

AU - Wong, Tin Lok

AU - Lee, Terence K

AU - Sharma, Rakesh

AU - Loong, Jane H

AU - Ching, Yick Pang

AU - Yuan, Yun-Fei

AU - Xie, Dan

AU - Lo, Chung Mau

AU - Man, Kwan

AU - Artegiani, Benedetta

AU - Clevers, Hans

AU - Yan, Helen H

AU - Leung, Suet Yi

AU - Richard, Stéphane

AU - Guan, Xin-Yuan

AU - Huen, Michael S Y

AU - Ma, Stephanie

PY - 2018/10/16

Y1 - 2018/10/16

N2 - Arginine methylation is a post-translational modification that plays pivotal roles in signal transduction and gene transcription during cell fate determination. We found protein methyltransferase 6 (PRMT6) to be frequently downregulated in hepatocellular carcinoma (HCC) and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis, and therapy resistance potential of HCC cell lines and patient-derived organoids. Consistently, loss of PRMT6 expression aggravated liver tumorigenesis in a chemical-induced HCC PRMT6 knockout (PRMT6-/-) mouse model. Integrated transcriptome and protein-protein interaction studies revealed an enrichment of genes implicated in RAS signaling and showed that PRMT6 interacted with CRAF on arginine 100, which decreased its RAS binding potential and altered its downstream MEK/ERK signaling. Our work describes a critical repressive function for PRMT6 in maintenance of HCC cells by regulating RAS binding and MEK/ERK signaling via methylation of CRAF on arginine 100.

AB - Arginine methylation is a post-translational modification that plays pivotal roles in signal transduction and gene transcription during cell fate determination. We found protein methyltransferase 6 (PRMT6) to be frequently downregulated in hepatocellular carcinoma (HCC) and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis, and therapy resistance potential of HCC cell lines and patient-derived organoids. Consistently, loss of PRMT6 expression aggravated liver tumorigenesis in a chemical-induced HCC PRMT6 knockout (PRMT6-/-) mouse model. Integrated transcriptome and protein-protein interaction studies revealed an enrichment of genes implicated in RAS signaling and showed that PRMT6 interacted with CRAF on arginine 100, which decreased its RAS binding potential and altered its downstream MEK/ERK signaling. Our work describes a critical repressive function for PRMT6 in maintenance of HCC cells by regulating RAS binding and MEK/ERK signaling via methylation of CRAF on arginine 100.

KW - Animals

KW - Apoptosis

KW - Carcinoma, Hepatocellular/genetics

KW - Cell Proliferation

KW - DNA Methylation

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Liver Neoplasms/genetics

KW - MAP Kinase Kinase 1/genetics

KW - MAP Kinase Signaling System

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred NOD

KW - Mice, Knockout

KW - Mice, Nude

KW - Mice, SCID

KW - Neoplastic Stem Cells/metabolism

KW - Nuclear Proteins/genetics

KW - Protein-Arginine N-Methyltransferases/genetics

KW - TNF Receptor-Associated Factor 3/genetics

KW - Tumor Cells, Cultured

KW - Xenograft Model Antitumor Assays

KW - raf Kinases/genetics

KW - ras Proteins/genetics

UR - http://www.scopus.com/inward/record.url?scp=85054755052&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2018.09.053

DO - 10.1016/j.celrep.2018.09.053

M3 - Article

C2 - 30332648

SN - 2211-1247

VL - 25

SP - 690-701.e8

JO - Cell reports

JF - Cell reports

IS - 3

ER -

PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation

Abstract

Keywords

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