NYMC Faculty Publications

Title

Demethylation of EHMT1/GLP Protein Reprograms Its Transcriptional Activity and Promotes Prostate Cancer Progression

Authors

Anna Besschetnova, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Wanting Han, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Mingyu Liu, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Yanfei Gao, Department of Orthopedics, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, P.R. China.
Muqing Li, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Zifeng Wang, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Maryam Labaf, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Susan Patalano, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Kavita Venkataramani, Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.
Rachel E. Muriph, Department of Chemistry, University of Massachusetts Boston, Boston, Massachusetts.
Jill A. Macoska, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Kellee R. Siegfried, Department of Biology, University of Massachusetts Boston, Boston, Massachusetts.
Jason Evans, Department of Chemistry, University of Massachusetts Boston, Boston, Massachusetts.
Steven P. Balk, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
Shuai Gao, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York.
Dong Han, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.
Changmeng Cai, Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, Massachusetts.

Author Type(s)

Faculty

First Page

1716

Last Page

1730

Document Type

Article

Publication Date

8-1-2023

Department

Cell Biology and Anatomy

Abstract

UNLABELLED: 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 and . 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.

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