组蛋白赖氨酸甲基转移酶和去甲基酶的失调是驱动去势抵抗型前列腺癌(CRPC)表观遗传重编程转录网络的主要机制之一。除了它们的经典组蛋白底物外，其中一些因子能够修饰关键转录因子，进一步影响致癌转录程序。我们最近的报告证明LSD1能够脱甲基化前列腺癌(PCa)细胞FOXA1的赖氨酸270位点，从而增强FOXA1染色质结合的稳定性。这个过程增强了雄激素受体和其他依赖于FOXA1作为开创性因子的转录因子的活性。然而，甲基转移酶负责FOXA1甲基化和FOXA1-LSD1致癌轴的负调节机制的身份仍然未知。SETD7最初通过甲基化组蛋白3赖氨酸4位点被鉴定为转录激活因子，但其在非组蛋白底物上的甲基转移酶功能仍知之甚少，特别是在PCa进展的背景下。在这项研究中，我们揭示了SETD7主要作为CRPC细胞中的转录抑制因子，通过作用于FOXA1-K270位点作为主要甲基转移酶。这种甲基化破坏了FOXA1介导的转录过程。与其分子功能一致，我们发现SETD7在PCa细胞中具有肿瘤抑制活性。此外，SETD7表达丢失与PCa进展和肿瘤侵袭性显著相关。总的来说，我们的研究为SETD7在介导PCa进展和治疗抵抗中的肿瘤抑制和转录抑制活性提供了机制上的见解。

Dysregulation of histone lysine methyltransferases and demethylases is one of the major mechanisms driving the epigenetic reprogramming of transcriptional networks in castration-resistant prostate cancer (CRPC). In addition to their canonical histone targets, some of these factors can modify critical transcription factors, further impacting oncogenic transcription programs. Our recent report demonstrated that LSD1 can demethylate the lysine 270 of FOXA1 in prostate cancer (PCa) cells, leading to the stabilization of FOXA1 chromatin binding. This process enhances the activities of the androgen receptor and other transcription factors that rely on FOXA1 as a pioneer factor. However, the identity of the methyltransferase responsible for FOXA1 methylation and negative regulation of the FOXA1-LSD1 oncogenic axis remains unknown. SETD7 was initially identified as a transcriptional activator through its methylation of histone 3 lysine 4, but its function as a methyltransferase on nonhistone substrates remains poorly understood, particularly in the context of PCa progression. In this study, we reveal that SETD7 primarily acts as a transcriptional repressor in CRPC cells by functioning as the major methyltransferase targeting FOXA1-K270. This methylation disrupts FOXA1-mediated transcription. Consistent with its molecular function, we found that SETD7 confers tumor suppressor activity in PCa cells. Moreover, loss of SETD7 expression is significantly associated with PCa progression and tumor aggressiveness. Overall, our study provides mechanistic insights into the tumor-suppressive and transcriptional repression activities of SETD7 in mediating PCa progression and therapy resistance.