VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway.
VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway.
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VHL 通过 HIF-1 α/HO-1 通路调节透明细胞肾细胞癌对 SIRT4 介导的代谢应激的敏感性
DOI：
10.1038/s41419-021-03901-7
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发表时间：
2021-06-16
影响因子：
9
通讯作者：
Lu R
中科院分区：
文献类型：
--
作者：
Tong Y;Kai J;Wang S;Yu Y;Xie S;Zheng H;Wang Y;Liu Y;Zhu K;Guan X;Guo L;Lu R
透明细胞肾细胞癌（ccRCC）重新编程对缺氧的碳代谢反应，从而促进谷氨酰胺的利用。近年来，sirtuin 4（SIRT 4）被发现与谷氨酰胺代谢和调节肿瘤微环境有关。然而，SIRT 4在ccRCC中的作用仍然知之甚少。在此，我们阐明了SIRT 4在癌组织中的表达显著降低，并且与恶性肿瘤的分期、分级和预后密切相关。在ccRCC细胞中，SIRT 4通过增强细胞内活性氧（ROS）发挥其促凋亡活性。血红素氧合酶-1（HO-1）是抗氧化应激的内源性防御系统的一部分。然而，SIRT 4的过表达阻碍HO-1在von Hippel-Lindau（VHL）-proficient细胞中的上调，并抑制其在VHL-缺陷细胞中的表达。这种差异表明，主管VHL承受SIRT 4对HIF-1α/HO-1的抑制作用。在功能上，HO-1的过表达抵消了SIRT 4对ROS积累和凋亡的促进作用。SIRT 4通过调节p38-MAPK磷酸化来调节ROS和HO-1的表达。与此相反，SB 203580下调p38-MAPK可降低细胞内ROS水平，增强HO-1的表达。总的来说，这项工作揭示了SIRT 4在刺激ROS和调节细胞凋亡中的潜在作用。SIRT 4/HO-1可能作为潜在的治疗靶点，特别是在VHL缺陷的ccRCC中。
Clear cell renal cell carcinomas (ccRCC) reprogram carbon metabolism responses to hypoxia, thereby promoting utilization of glutamine. Recently, sirtuin 4 (SIRT4), a novel molecular has turned out to be related to alternating glutamine metabolism and modulating the tumor microenvironment. However, the role of SIRT4 in ccRCC remains poorly understood. Here, we illustrated that the expression of SIRT4 is markedly reduced in cancerous tissues, and closely associated with malignancy stage, grade, and prognosis. In ccRCC cells, SIRT4 exerted its proapoptotic activity through enhancing intracellular reactive oxygen species (ROS). Heme oxygenase-1 (HO-1) is part of an endogenous defense system against oxidative stress. Nevertheless, overexpression of SIRT4 hindered the upregulation of HO-1 in von Hippel–Lindau (VHL)-proficient cells and repressed its expression in VHL-deficient cells. This discrepancy indicated that competent VHL withstands the inhibitory role of SIRT4 on HIF-1α/HO-1. Functionally, overexpression of HO-1 counteracted the promotional effects of SIRT4 on ROS accumulation and apoptosis. Mechanistically, SIRT4 modulates ROS and HO-1 expression via accommodating p38-MAPK phosphorylation. By contrast, downregulation of p38-MAPK by SB203580 decreased intracellular ROS level and enhanced the expression of HO-1. Collectively, this work revealed a potential role for SIRT4 in the stimulation of ROS and the modulation of apoptosis. SIRT4/HO-1 may act as a potential therapeutic target, especially in VHL-deficient ccRCCs.
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影响因子：
4.7
作者：
Briston T;Stephen JM;Thomas LW;Esposito C;Chung YL;Syafruddin SE;Turmaine M;Maddalena LA;Greef B;Szabadkai G;Maxwell PH;Vanharanta S;Ashcroft M
通讯作者：
Ashcroft M
影响因子：
4.8
作者：
Abdelbaset-Ismail A;Cymer M;Borkowska-Rzeszotek S;Brzeźniakiewicz-Janus K;Rameshwar P;Kakar SS;Ratajczak J;Ratajczak MZ
通讯作者：
Ratajczak MZ
DOI：
10.1152/ajplung.00167.2014
发表时间：
2014-11-15
影响因子：
4.9
作者：
Chillappagari, Shashi;Venkatesan, Shalini;Henke, Markus O.
通讯作者：
Henke, Markus O.
影响因子：
19.6
作者：
Goodman, A. I.;Olszanecki, R.;Abraham, N. G.
通讯作者：
Abraham, N. G.
DOI：
10.1016/j.bbrc.2016.01.078
发表时间：
2016-02-05
影响因子：
3.1
作者：
Jeong, Seung Min;Hwang, Sunsook;Seong, Rho Hyun
通讯作者：
Seong, Rho Hyun