Serine metabolic reprogramming is known to be associated with oncogenesis and tumor development. The key metabolic enzyme PSAT1 has been identified as a potential prognostic marker for various cancers, but its role in ccRCC remains unkown. In this study, we investigated expression of PSAT1 in ccRCC using the TCGA database and clinical specimens. Our results showed that PSAT1 exhibited lower expression in tumor tissue compared to adjacent normal tissue, but its expression level increased with advancing stages and grades of ccRCC. Patients with elevated expression level of PSAT1 exhibited an unfavorable prognosis. Functional experiments have substantiated that the depletion of PSAT1 shows an effective activity in inhibiting the proliferation, migration and invasion of ccRCC cells, concurrently promoting apoptosis. RNA sequencing analysis has revealed that the attenuation of PSAT1 can diminish tumor resistance to therapeutic drugs. Furthermore, the xenograft model has indicated that the inhibition of PSAT1 can obviously impact the tumorigenic potential of ccRCC and mitigate lung metastasis. Notably, pharmacological targeting PSAT1 by Aminooxyacetic Acid (AOA) or knockdown of PSAT1 increased the susceptibility of sunitinib-resistant cells. Inhibition of PSAT1 increased the sensitivity of drug-resistant tumors to sunitinib in vivo. Collectively, our investigation identifies PSAT1 as an independent prognostic biomarker for advanced ccRCC patients and as a prospective therapeutic target.

中文翻译：

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丝氨酸代谢酶PSAT1的上调预测不良预后并促进透明细胞肾细胞癌的增殖、转移和耐药

已知丝氨酸代谢重编程与肿瘤发生和肿瘤发展相关。关键代谢酶 PSAT1 已被确定为多种癌症的潜在预后标志物，但其在 ccRCC 中的作用仍不清楚。在本研究中，我们使用 TCGA 数据库和临床标本研究了 ccRCC 中 PSAT1 的表达。我们的结果表明，与邻近正常组织相比，PSAT1 在肿瘤组织中的表达较低，但其表达水平随着 ccRCC 分期和级别的进展而增加。 PSAT1表达水平升高的患者预后不良。功能实验证实，PSAT1的缺失可有效抑制ccRCC细胞的增殖、迁移和侵袭，同时促进细胞凋亡。 RNA测序分析表明，PSAT1的减弱可以降低肿瘤对治疗药物的耐药性。此外，异种移植模型表明，抑制PSAT1可以明显影响ccRCC的致瘤潜力并减轻肺转移。值得注意的是，通过氨氧乙酸 (AOA) 靶向 PSAT1 或敲除 PSAT1 的药物会增加舒尼替尼耐药细胞的敏感性。抑制 PSAT1 会增加体内耐药肿瘤对舒尼替尼的敏感性。总的来说，我们的研究将 PSAT1 确定为晚期 ccRCC 患者的独立预后生物标志物和前瞻性治疗靶点。