KDELR2 promotes breast cancer proliferation via HDAC3-mediated cell cycle progression.
KDELR2 promotes breast cancer proliferation via HDAC3-mediated cell cycle progression.
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DOI：
10.1002/cac2.12180
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Zhong X
中科院分区：
文献类型：
--
作者：
Wei H;Ma W;Lu X;Liu H;Lin K;Wang Y;Ye Z;Sun L;Huang Z;Pan T;Zhou Z;Cheng EY;Zhang H;Gao P;Zhong X
组蛋白脱乙酰酶（HDAC）通过控制全局基因表达参与各种细胞过程的调节。HDAC的失调导致致癌，使HDAC成为癌症治疗的理想靶标。然而，在临床研究中，HDAC抑制剂（HDACi）作为单一药剂的使用已显示在治疗实体瘤中具有有限的成功。本研究旨在鉴定HDAC的新型下游效应物，以提供联合治疗的潜在靶点。进行转录组测序和生物信息学分析以筛选乳腺癌细胞中响应HDACi的基因。MTT法检测HDACi对细胞活力的影响。通过定量逆转录-PCR（qRT-PCR）和蛋白质印迹法测定基因的mRNA和蛋白质水平。流式细胞仪分析细胞周期分布及凋亡情况。通过ChIP（染色质免疫沉淀试验）验证CREB 1（cAMP-反应元件结合蛋白1）与KDELR（KDEL（Lys-Asp-Glu-Leu）受体）基因启动子的结合。免疫沉淀法检测KDELR 2与中心粒5蛋白（POC 5）的结合。采用携带乳腺癌的小鼠模型来分析HDAC 3-KDELR 2轴对肿瘤生长的影响。KDELR 2是HDAC 3的新靶点，其异常表达提示乳腺癌患者预后不良。我们发现乳腺癌患者肿瘤组织中HADC 3和KDELR 2的蛋白表达模式之间存在很强的相关性。ChIP试验和qRT-PCR分析的结果验证了HDAC 3通过CREB 1反式激活KDELR 2。HDAC 3-KDELR 2轴通过保护中心体蛋白POC 5免受蛋白酶体降解而加速癌细胞的细胞周期进程。此外，HDAC 3-KDELR 2轴在体外和体内促进乳腺癌细胞增殖和肿瘤发生。我们的研究结果揭示了KDELR 2在肿瘤发生中以前未被重视的功能，将关键的高尔基体-内质网运输蛋白与癌症发展路径上的HDAC控制的细胞周期进展联系起来，从而揭示了乳腺癌的潜在治疗靶点。
Histone deacetylases (HDACs) engage in the regulation of various cellular processes by controlling global gene expression. The dysregulation of HDACs leads to carcinogenesis, making HDACs ideal targets for cancer therapy. However, the use of HDAC inhibitors (HDACi) as single agents has been shown to have limited success in treating solid tumors in clinical studies. This study aimed to identify a novel downstream effector of HDACs to provide a potential target for combination therapy. Transcriptome sequencing and bioinformatics analysis were performed to screen for genes responsive to HDACi in breast cancer cells. The effects of HDACi on cell viability were detected using the MTT assay. The mRNA and protein levels of genes were determined by quantitative reverse transcription‐PCR (qRT‐PCR) and Western blotting. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The binding of CREB1 (cAMP‐response element binding protein 1) to the promoter of the KDELR (The KDEL (Lys‐Asp‐Glu‐Leu) receptor) gene was validated by the ChIP (chromatin immunoprecipitation assay). The association between KDELR2 and protein of centriole 5 (POC5) was detected by immunoprecipitation. A breast cancer‐bearing mouse model was employed to analyze the effect of the HDAC3‐KDELR2 axis on tumor growth. KDELR2 was identified as a novel target of HDAC3, and its aberrant expression indicated the poor prognosis of breast cancer patients. We found a strong correlation between the protein expression patterns of HADC3 and KDELR2 in tumor tissues from breast cancer patients. The results of the ChIP assay and qRT‐PCR analysis validated that HDAC3 transactivated KDELR2 via CREB1. The HDAC3‐KDELR2 axis accelerated the cell cycle progression of cancer cells by protecting the centrosomal protein POC5 from proteasomal degradation. Moreover, the HDAC3‐KDELR2 axis promoted breast cancer cell proliferation and tumorigenesis in vitro and in vivo. Our results uncovered a previously unappreciated function of KDELR2 in tumorigenesis, linking a critical Golgi‐the endoplasmic reticulum traffic transport protein to HDAC‐controlled cell cycle progression on the path of cancer development and thus revealing a potential therapeutical target for breast cancer.
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影响因子：
4.1
作者：
McGee-Lawrence, Meghan E.;White, Thomas A.;LeBrasseur, Nathan K.;Westendorf, Jennifer J.
通讯作者：
Westendorf, Jennifer J.
影响因子：
13.6
作者：
Le Guennec, Maeva;Klena, Nikolai;Guichard, Paul
通讯作者：
Guichard, Paul
影响因子：
4.8
作者：
Henderson, Mark J.;Richie, Christopher T.;Harvey, Brandon K.
通讯作者：
Harvey, Brandon K.
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Hsu VW;Shah N;Klausner RD
通讯作者：
Klausner RD