Date of Award

5-2023

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology/Molecular, Cellular, and Organismal Biology

First Advisor

Changmeng Cai

Second Advisor

Jill Macoska

Third Advisor

Jens Rister

Abstract

Post-translational Modifications, and specifically lysine methylations of histones, are critical to regulating the epigenetic transcription programming. In Prostate cancer (PCa), many lysine methyltransferases and lysine demethylases are aberrantly expressed or altered, leading to advanced progression of PCa. By performing a screening study to identify novel lysine methylations in PCa cells, we discovered methylated lysine 450 and 451 at the EHMT1/GLP protein, which is a lysine methyltransferase known for mono and di-methylating histone 3 lysine 9 and primarily functions as a transcriptional repressor. While the EHMT1 gene is expressed in higher levels in advanced Castration-Resistant Prostate Cancer (CRPC), very little is known about its role and regulation in PCa progression. I found that a known chromatin remodeler and lysine demethylase, LSD1, can demethylate the K450me site. Notably, the dual demethylation of both K450me and K451me expands the chromatin binding of EHMT1 globally and switches EHMT1 into a transcription activator in PCa cells to activate oncogenic signaling pathways. Through acting on these pathways, silencing EHMT1 with RNAi or using inhibitors on EHMT1 activity can markedly decrease PCa cell proliferation and metastasis in vitro and in vivo. In addition to these studies, I also performed mass-spectrometry analysis to identify specific interacting proteins of methylated and unmethylated EHMT1 and attempted to identify the core amino acid sequences that are required for substrate recognition by LSD1. Overall, my studies suggest that the dual-lysine demethylation of EHMT1 can function as a molecular switch to induce oncogenic transcriptional reprogramming in PCa cells.

Comments

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