Due to the limited effectiveness of current treatments, the survival rate of patients with metastatic castration-resistant prostate cancer (mCRPC) is significantly reduced. Consequently, it is imperative to identify novel therapeutic targets for managing these patients. Since the invasive ability of cells is crucial for establishing and maintaining metastasis, the aim of this study was to identify the essential regulators of invasive abilities of mCRPC cells by conducting two independent high-throughput CRISPR/Cas9 screenings. Furthermore, some of the top hits were validated using siRNA technology, with protein arginine methyltransferase 7 (PRMT7) emerging as the most promising candidate. We demonstrated that its inhibition or depletion via genetic or pharmacological approaches significantly reduces invasive, migratory and proliferative abilities of mCRPC cells . Moreover, we confirmed that ablation reduces cell dissemination in chicken chorioallantoic membrane and mouse xenograft assays. Molecularly, PRMT7 reprograms the expression of several adhesion molecules by methylating various transcription factors, such as FoxK1, resulting in the loss of adhesion from the primary tumor and increased motility of mCRPC cells. Furthermore, higher expression correlates with tumor aggressivity and poor overall survival in prostate cancer patients. Thus, this study demonstrates that is a potential therapeutic target and potential biomarker for mPCa.

中文翻译：

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CRISPR/Cas9 筛选发现蛋白质精氨酸甲基转移酶 7 是前列腺癌转移中的一种新型必需基因

由于目前治疗的有效性有限，转移性去势抵抗性前列腺癌（mCRPC）患者的生存率显着降低。因此，必须确定新的治疗靶点来管理这些患者。由于细胞的侵袭能力对于建立和维持转移至关重要，因此本研究的目的是通过进行两次独立的高通量 CRISPR/Cas9 筛选来确定 mCRPC 细胞侵袭能力的重要调节因子。此外，一些热门产品已使用 siRNA 技术进行了验证，其中蛋白质精氨酸甲基转移酶 7 (PRMT7) 成为最有前途的候选者。我们证明，通过遗传或药理学方法抑制或消除它可以显着降低 mCRPC 细胞的侵袭、迁移和增殖能力。此外，我们证实，在鸡绒毛尿囊膜和小鼠异种移植试验中，消融可减少细胞传播。从分子角度来看，PRMT7 通过甲基化各种转录因子（例如 FoxK1）来重新编程多种粘附分子的表达，导致原发肿瘤的粘附力丧失并增加 mCRPC 细胞的运动性。此外，较高的表达与前列腺癌患者的肿瘤侵袭性和较差的总体生存率相关。因此，这项研究表明这是 mPCa 的潜在治疗靶点和潜在生物标志物。