Demethylation of EHMT1/GLP Protein Reprograms Its Transcriptional Activity and Promotes Prostate Cancer Progression.
| Title: | Demethylation of EHMT1/GLP Protein Reprograms Its Transcriptional Activity and Promotes Prostate Cancer Progression. |
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| Authors: | Besschetnova A; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Han W; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington.; Liu M; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Gao Y; Department of Orthopedics, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China.; Li M; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Wang Z; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Labaf M; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Mathematics, University of Massachusetts Boston, Boston, Massachusetts.; Patalano S; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Venkataramani K; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Muriph RE; Department of Chemistry, University of Massachusetts Boston, Boston, Massachusetts.; Macoska JA; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Siegfried KR; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Evans J; Department of Chemistry, University of Massachusetts Boston, Boston, Massachusetts.; Balk SP; Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.; Gao S; Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York.; Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York.; Han D; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.; Cai C; Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.; Department of Biology, University of Massachusetts Boston, Boston, Massachusetts. |
| Source: | Cancer research communications [Cancer Res Commun] 2023 Aug 31; Vol. 3 (8), pp. 1716-1730. Date of Electronic Publication: 2023 Aug 31 (Print Publication: 2023). |
| Publication Type: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| Language: | English |
| Journal Info: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 9918281580506676 Publication Model: eCollection Cited Medium: Internet ISSN: 2767-9764 (Electronic) Linking ISSN: 27679764 NLM ISO Abbreviation: Cancer Res Commun Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Philadelphia, Pennsylvania] : American Association for Cancer Research, [2021]- |
| MeSH Terms: | Prostatic Neoplasms*/genetics ; Prostatic Hyperplasia*; Histone-Lysine N-Methyltransferase/genetics ; Male ; Humans ; Lysine ; Histones ; Neoplastic Processes ; Chromatin ; Demethylation ; Histocompatibility Antigens |
| Abstract: | Epigenetic reprogramming, mediated by genomic alterations and dysregulation of histone reader and writer proteins, plays a critical role in driving prostate cancer progression and treatment resistance. However, the specific function and regulation of EHMT1 (also known as GLP) and EHMT2 (also known as G9A), well-known histone 3 lysine 9 methyltransferases, in prostate cancer progression remain poorly understood. Through comprehensive investigations, we discovered that both EHMT1 and EHMT2 proteins have the ability to activate oncogenic transcription programs in prostate cancer cells. Silencing EHMT1/2 or targeting their enzymatic activity with small-molecule inhibitors can markedly decrease prostate cancer cell proliferation and metastasis in vitro and in vivo. In-depth analysis of posttranslational modifications of EHMT1 protein revealed the presence of methylation at lysine 450 and 451 residues in multiple prostate cancer models. Notably, we found that lysine 450 can be demethylated by LSD1. Strikingly, concurrent demethylation of both lysine residues resulted in a rapid and profound expansion of EHMT1's chromatin binding capacity, enabling EHMT1 to reprogram the transcription networks in prostate cancer cells and activate oncogenic signaling pathways. Overall, our studies provide valuable molecular insights into the activity and function of EHMT proteins during prostate cancer progression. Moreover, we propose that the dual-lysine demethylation of EHMT1 acts as a critical molecular switch, triggering the induction of oncogenic transcriptional reprogramming in prostate cancer cells. These findings highlight the potential of targeting EHMT1/2 and their demethylation processes as promising therapeutic strategies for combating prostate cancer progression and overcoming treatment resistance.; Significance: In this study, we demonstrate that EHMT1 and EHMT2 proteins drive prostate cancer development by transcriptionally activating multiple oncogenic pathways. Mechanistically, the chromatin binding of EHMT1 is significantly expanded through demethylation of both lysine 450 and 451 residues, which can serve as a critical molecular switch to induce oncogenic transcriptional reprogramming in prostate cancer cells.; (© 2023 The Authors; Published by the American Association for Cancer Research.) |
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| Grant Information: | P01 CA163227 United States CA NCI NIH HHS; P50 CA090381 United States CA NCI NIH HHS; R01 CA211350 United States CA NCI NIH HHS; U54 CA156734 United States CA NCI NIH HHS |
| Substance Nomenclature: | K3Z4F929H6 (Lysine); 0 (Histones); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase); 0 (Chromatin); EC 2.1.1.43 (EHMT2 protein, human); 0 (Histocompatibility Antigens); EC 2.1.1.- (EHMT1 protein, human) |
| Entry Date(s): | Date Created: 20230904 Date Completed: 20230905 Latest Revision: 20230912 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10470473 |
| DOI: | 10.1158/2767-9764.CRC-23-0208 |
| PMID: | 37663929 |
| Database: | MEDLINE |
Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural