@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 = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = mar,
day = "18",
doi = "10.1016/j.molcel.2021.01.015",
language = "English (US)",
volume = "81",
pages = "1276--1291.e9",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}
