PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells

Tianzhi Huang; Yongyong Yang; Xiao Song; Xuechao Wan; Bingli Wu; Namratha Sastry; Craig M. Horbinski; Chang Zeng; Deanna Tiek; Anshika Goenka; Fabao Liu; Cameron W. Brennan; John A. Kessler; Roger Stupp; Ichiro Nakano; Erik P. Sulman; Ryo Nishikawa; Charles David James; Wei Zhang; Wei Xu; Bo Hu; Shi Yuan Cheng

doi:10.1016/j.molcel.2021.01.015

PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells

Tianzhi Huang, Yongyong Yang, Xiao Song, Xuechao Wan, Bingli Wu, Namratha Sastry, Craig M. Horbinski, Chang Zeng, Deanna Tiek, Anshika Goenka, Fabao Liu, Cameron W. Brennan, John A. Kessler, Roger Stupp, Ichiro Nakano, Erik P. Sulman, Ryo Nishikawa, Charles David James, Wei Zhang, Wei XuBo Hu^*, Shi Yuan Cheng

^*Corresponding author for this work

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

72 Scopus citations

Abstract

Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.

Original language	English (US)
Pages (from-to)	1276-1291.e9
Journal	Molecular cell
Volume	81
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2021.01.015
State	Published - Mar 18 2021

Funding

All shared resources at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, that contributed to this study were supported by National Cancer Institute (NCI) Cancer Center grant P30CA060553 . The Northwestern Nervous System Tumor Bank was supported by NIH grant P50CA221747 . We thank Dr. EG Van Meir and Dr. Evelyne Manet for providing reagents. This work was also supported by NIH grants NS093843 , NS095634 , and NS115403 (S.-Y.C.); CA209345 (W.Z. and S.-Y.C); CA213293 and CA236356 (W.X.); CA201402 and NS107071 (I.N.); NS095642 (C.D.J.); AG054429 (J.A.K.); and NS102669 and NS117104 (C.M.H.); and The Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine (S.-Y.C. and B.H.). N.S. and D.T. were supported by the NIH under awards F31CA232630 (N.S.) and K00CA234799 (D.T.). S.-Y.C. is a Zell Scholar at Northwestern University. The authors thank Northwestern University Center for Advanced Microscope and Proteomics Core Facility for help with imaging and proteomics experiments. All shared resources at the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, that contributed to this study were supported by National Cancer Institute (NCI) Cancer Center grant P30CA060553. The Northwestern Nervous System Tumor Bank was supported by NIH grant P50CA221747. We thank Dr. EG Van Meir and Dr. Evelyne Manet for providing reagents. This work was also supported by NIH grants NS093843, NS095634, and NS115403 (S.-Y.C.); CA209345 (W.Z. and S.-Y.C); CA213293 and CA236356 (W.X.); CA201402 and NS107071 (I.N.); NS095642 (C.D.J.); AG054429 (J.A.K.); and NS102669 and NS117104 (C.M.H.); and The Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine (S.-Y.C. and B.H.). N.S. and D.T. were supported by the NIH under awards F31CA232630 (N.S.) and K00CA234799 (D.T.). S.-Y.C. is a Zell Scholar at Northwestern University. The authors thank Northwestern University Center for Advanced Microscope and Proteomics Core Facility for help with imaging and proteomics experiments. Conceptualization, S.-Y.C. B.H. T.H. and Y.Y.; Methodology, S.-Y.C. B.H. T.H. Y.Y. and W.X.; Formal Analysis, T.H. S.-Y.C. B.H. Y.Y. X.S. X.W. B.W. C.Z. N.S. D.T. A.G. W.Z. and W.X.; Investigation, T.H. Y.Y. X.S. X.W. B.W. and N.S.; Resources, W.X. F.L. C.M.H. J.A.K. R.N. I.N. C.D.J. C.W.B. and E.P.S.; Writing ? Original Draft, T.H. S.-Y.C. and B.H.; Writing ? Review & Editing, T.H. S.-Y.C. C.D.J. B.H. Y.Y. X.S. B.W. C.Z. N.S. D.T. A.G. W.X. C.M.H. J.A.K. R.S. I.N. E.P.S. W.Z. and C.W.B.; Supervision, S.-Y.C. and B.H.; Project Administration, S.-Y.C. and B.H.; Funding Acquisition, S.-Y.C. and B.H. The authors, and their immediate family members, are not members of the Molecular Cell advisory board. The authors declare no further competing interests.

Keywords

CK2
GBM
GSC
PRMT
RCC1
arginine methylation
mitosis
phosphorylation
therapy response
tumorigenicity

ASJC Scopus subject areas

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.molcel.2021.01.015

Cite this

Huang, T., Yang, Y., Song, X., Wan, X., Wu, B., Sastry, N., Horbinski, C. M., Zeng, C., Tiek, D., Goenka, A., Liu, F., Brennan, C. W., Kessler, J. A., Stupp, R., Nakano, I., Sulman, E. P., Nishikawa, R., James, C. D., Zhang, W., ... Cheng, S. Y. (2021). PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells. Molecular cell, 81(6), 1276-1291.e9. https://doi.org/10.1016/j.molcel.2021.01.015

@article{75557a5f5c9d45a486f96b3e411910ec,

title = "PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells",

abstract = "Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.",

keywords = "CK2, GBM, GSC, PRMT, RCC1, arginine methylation, mitosis, phosphorylation, therapy response, tumorigenicity",

author = "Tianzhi Huang and Yongyong Yang and Xiao Song and Xuechao Wan and Bingli Wu and Namratha Sastry and Horbinski, {Craig M.} and Chang Zeng and Deanna Tiek and Anshika Goenka and Fabao Liu and Brennan, {Cameron W.} and Kessler, {John A.} and Roger Stupp and Ichiro Nakano and Sulman, {Erik P.} and Ryo Nishikawa and James, {Charles David} and Wei Zhang and Wei Xu and Bo Hu and Cheng, {Shi Yuan}",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = mar,

day = "18",

doi = "10.1016/j.molcel.2021.01.015",

language = "English (US)",

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pages = "1276--1291.e9",

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Huang, T, Yang, Y, Song, X, Wan, X, Wu, B, Sastry, N, Horbinski, CM, Zeng, C, Tiek, D, Goenka, A, Liu, F, Brennan, CW, Kessler, JA , Stupp, R, Nakano, I, Sulman, EP, Nishikawa, R, James, CD , Zhang, W, Xu, W, Hu, B & Cheng, SY 2021, 'PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells', Molecular cell, vol. 81, no. 6, pp. 1276-1291.e9. https://doi.org/10.1016/j.molcel.2021.01.015

TY - JOUR

T1 - PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells

AU - Huang, Tianzhi

AU - Yang, Yongyong

AU - Song, Xiao

AU - Wan, Xuechao

AU - Wu, Bingli

AU - Sastry, Namratha

AU - Horbinski, Craig M.

AU - Zeng, Chang

AU - Tiek, Deanna

AU - Goenka, Anshika

AU - Liu, Fabao

AU - Brennan, Cameron W.

AU - Kessler, John A.

AU - Stupp, Roger

AU - Nakano, Ichiro

AU - Sulman, Erik P.

AU - Nishikawa, Ryo

AU - James, Charles David

AU - Zhang, Wei

AU - Xu, Wei

AU - Hu, Bo

AU - Cheng, Shi Yuan

PY - 2021/3/18

Y1 - 2021/3/18

N2 - Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.

AB - Aberrant cell proliferation is a hallmark of cancer, including glioblastoma (GBM). Here we report that protein arginine methyltransferase (PRMT) 6 activity is required for the proliferation, stem-like properties, and tumorigenicity of glioblastoma stem cells (GSCs), a subpopulation in GBM critical for malignancy. We identified a casein kinase 2 (CK2)-PRMT6-regulator of chromatin condensation 1 (RCC1) signaling axis whose activity is an important contributor to the stem-like properties and tumor biology of GSCs. CK2 phosphorylates and stabilizes PRMT6 through deubiquitylation, which promotes PRMT6 methylation of RCC1, which in turn is required for RCC1 association with chromatin and activation of RAN. Disruption of this pathway results in defects in mitosis. EPZ020411, a specific small-molecule inhibitor for PRMT6, suppresses RCC1 arginine methylation and improves the cytotoxic activity of radiotherapy against GSC brain tumor xenografts. This study identifies a CK2α-PRMT6-RCC1 signaling axis that can be therapeutically targeted in the treatment of GBM.

KW - CK2

KW - GBM

KW - GSC

KW - PRMT

KW - RCC1

KW - arginine methylation

KW - mitosis

KW - phosphorylation

KW - therapy response

KW - tumorigenicity

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U2 - 10.1016/j.molcel.2021.01.015

DO - 10.1016/j.molcel.2021.01.015

M3 - Article

C2 - 33539787

AN - SCOPUS:85101175221

SN - 1097-2765

VL - 81

SP - 1276-1291.e9

JO - Molecular cell

JF - Molecular cell

IS - 6

ER -

PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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