表观遗传重编程，由基因组改变和组蛋白阅读和编写蛋白质的失调介导，在推动前列腺癌进展和治疗耐药中起着关键作用。然而，前列腺癌进展中EHMT1（又称GLP）和EHMT2（又称G9A）这两种众所周知的组蛋白3赖氨酸9甲基转移酶的特定功能和调控仍然知之甚少。通过全面调查，我们发现EHMT1和EHMT2蛋白质都具备在前列腺癌细胞中激活致癌转录程序的能力。通过沉默EHMT1/2或用小分子抑制剂靶向它们的酶活性，可以显著降低前列腺癌细胞的增殖和转移能力，不论是体外还是体内。对EHMT1蛋白的翻译后修饰进行深入分析揭示了在多种前列腺癌模型中赖氨酸450和451残基的甲基化。值得注意的是，我们发现赖氨酸450可以被LSD1去甲基化。引人注目的是，同时去甲基化这两个赖氨酸残基导致EHMT1的染色质结合能力迅速而深远地扩大，使EHMT1能够重新编程前列腺癌细胞的转录网络并激活致癌信号通路。总的来说，我们的研究为EHMT蛋白在前列腺癌进展中的活性和功能提供了宝贵的分子洞察。此外，我们提出EHMT1的双赖氨酸去甲基化作为一个关键的分子开关，触发前列腺癌细胞中致癌转录重编程的诱导。这些发现凸显了以EHMT1/2及其去甲基化过程为靶点的潜在治疗策略，用于抗击前列腺癌进展和克服治疗耐药。本研究证明，EHMT1和EHMT2蛋白通过转录活化多个致癌通路推动前列腺癌的发展。机制上，通过去甲基化赖氨酸450和451残基，EHMT1的染色质结合显著扩大，这可作为在前列腺癌细胞中诱导致癌转录重编程的关键分子开关。© 2023作者；美国癌症研究协会出版。

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.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.