Guo Renbo, Liang Yiran, Zou Benkui, Li Danyang, Wu Zhen, Xie Fei, Zhang Xu, Li Xiangzhi
Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Shandong University, Qingdao, China.
Department of Urology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Front Oncol. 2022 Feb 16;12:842967. doi: 10.3389/fonc.2022.842967. eCollection 2022.
Renal cell carcinoma (RCC) is one of the most common and lethal human urological malignancies around the world. Although many advancements in diagnostic and therapeutic strategies have been acquired, the prognosis of patients with metastatic RCC was poor. Thus, there is an urgent need to understand the molecular mechanism of RCC.
The quantitative real-time PCR (qRT-PCR) was used to detect the RNA expression of MOF in human RCC tissues and cell lines. The protein expression of MOF was analyzed with immunohistochemistry (IHC) and Western blot. To understand the regulatory mechanism of MOF in liver cancer, ChIP-qPCR assay and dual-luciferase assay were performed. Moreover, a series of and experiments were conducted to evaluate the effect of MOF on renal cell carcinoma progression.
In the present study, we found that Males absent on the first (MOF), a histone acetyltransferase involved in transcription activation, was significantly decreased in both RCC tissues and RCC cells compared to normal tissues and non-cancer cells. Moreover, MOF downregulation was associated with advanced histological grade, pathologic stage and distant metastasis of RCC patients. Ectopic expression of MOF could significantly attenuate cell proliferation and promote cell apoptosis. Besides, MOF overexpression also suppressed migration of RCC cells through inhibiting epithelial-mesenchymal transition (EMT). Importantly, the inhibition of tumor growth by MOF was further confirmed by studies. Mechanism dissection revealed that MOF could transcriptionally upregulate the expression of SIRT1, leading to attenuated STAT3 signaling, which was involved in cell proliferation and migration. Moreover, SIRT1 knockdown could restore the biological function induced by MOF overexpression.
Our findings indicated that MOF serves as a tumor suppressor regulation of SIRT1 in the development and progression of RCC, and MOF might be a potent biomarker for diagnosis and prognosis prediction of RCC patients.
肾细胞癌（RCC）是全球最常见且致命的人类泌尿系统恶性肿瘤之一。尽管在诊断和治疗策略方面已取得许多进展，但转移性肾细胞癌患者的预后仍然很差。因此，迫切需要了解肾细胞癌的分子机制。
采用定量实时聚合酶链反应（qRT-PCR）检测人肾细胞癌组织和细胞系中MOF的RNA表达。用免疫组织化学（IHC）和蛋白质免疫印迹法分析MOF的蛋白表达。为了解MOF在肝癌中的调控机制，进行了染色质免疫沉淀-定量聚合酶链反应（ChIP-qPCR）分析和双荧光素酶分析。此外，进行了一系列体内和体外实验以评估MOF对肾细胞癌进展的影响。
在本研究中，我们发现参与转录激活的组蛋白乙酰转移酶第一雄性缺失蛋白（MOF）在肾细胞癌组织和细胞中均比正常组织和非癌细胞显著降低。此外，MOF下调与肾细胞癌患者的高级组织学分级、病理分期和远处转移相关。MOF的异位表达可显著减弱细胞增殖并促进细胞凋亡。此外，MOF过表达还通过抑制上皮-间质转化（EMT）抑制肾癌细胞的迁移。重要的是，体内研究进一步证实了MOF对肿瘤生长的抑制作用。机制剖析显示，MOF可转录上调SIRT1的表达，导致STAT3信号减弱，而STAT3信号与细胞增殖和迁移有关。此外，敲低SIRT1可恢复MOF过表达诱导的生物学功能。
我们的研究结果表明，MOF在肾细胞癌的发生发展过程中作为一种肿瘤抑制因子通过调控SIRT1发挥作用，并且MOF可能是肾细胞癌患者诊断和预后预测的有效生物标志物。
