Human Ccr4 and Caf1 Deadenylases Regulate Proliferation and Tumorigenicity of Human Gastric Cancer Cells via Modulating Cell Cycle Progression.
Human Ccr4 and Caf1 Deadenylases Regulate Proliferation and Tumorigenicity of Human Gastric Cancer Cells via Modulating Cell Cycle Progression.
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人 Ccr4 和 Caf1 脱腺苷酸酶通过调节细胞周期进程来调节人胃癌细胞的增殖和致瘤性
DOI：
10.3390/cancers13040834
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发表时间：
2021-02-17
期刊：
影响因子：
5.2
通讯作者：
Yan YB
中科院分区：
文献类型：
--
作者：
Song XH;Liao XY;Zheng XY;Liu JQ;Zhang ZW;Zhang LN;Yan YB
简单概述癌细胞通常重新编程它们的基因表达谱以满足持续的生长、增殖和转移。大多数真核生物的mRNAs是以依赖于死烯基化的途径降解的，其中死烯基酶是关键酶。我们发现人CCR4(hCcr4a/b)和CAF1(hCaf1a/b)这两种主要的胞浆死烯基酶在包括胃腺癌在内的几种癌症中都存在调控异常。稳定地敲除hCaf1a/b或hCcr4a/b通过提高细胞周期抑制物的水平和抑制与mRNA代谢有关的胞浆焦点的形成来阻止细胞周期的进展。更重要的是，hCaf1a/b或hCcr4a/b的缺失会显著抑制细胞的增殖和致瘤性。我们的结果表明，干扰全球RNA代谢可能为癌症治疗提供一种潜在的新策略。摘要癌细胞通常具有重新编程的基因表达谱，以满足生存、持续分裂和转移的要求。一个有趣的问题是，癌细胞是否会受到干扰其全球RNA新陈代谢的影响。在这项研究中，我们发现人Ccr4a/b(hCcr4a/b)和Caf1a/b(hCaf1a/b)Deadenylase是CCR4-NOT复合体的催化成分，在包括胃腺癌在内的几种癌症中都存在调控失调。通过建立4个稳定的hCcr4a/b或hCaf1a/b基因敲除的MKN28细胞系或在多个细胞系中瞬时敲除hCaf1a/b基因的方法，研究了4种Deadenylase对癌细胞生长的影响。HCcr4a/b或hCaf1a/b缺失可显著抑制细胞增殖和致瘤性。机制研究表明，hCaf1a被阻断后，细胞被阻滞在G2/M期，而hCaf1b或hCcr4a/b被阻断在G0/G1期。这四种酶不影响CDK和Cyclins的水平，但调节CDK-Cyclin抑制物的水平。我们发现hCcr4a/b而不是hCaf1a/b靶向于MKN28细胞中的p21mRNA。此外，四种枯烯基酶中的任何一种的缺失都会显著损害MKN28和HEK-293T细胞中的加工体形成。我们的结果表明，干扰全球RNA代谢可能严重影响癌细胞的增殖，这为癌症治疗提供了一种潜在的新策略。
Simple Summary Cancer cells generally reprogram their gene expression profiles to satisfy continuous growth, proliferation, and metastasis. Most eukaryotic mRNAs are degraded in a deadenylation-dependent pathway, in which deadenylases are the key enzymes. We found that human Ccr4 (hCcr4a/b) and Caf1 (hCaf1a/b), the dominant cytosolic deadenylases, were dysregulated in several types of cancers including stomach adenocarcinoma. Stably knocking down hCaf1a/b or hCcr4a/b blocks cell cycle progression by enhancing the levels of cell cycle inhibitors and by inhibiting the formation of processing bodies, which are cytosolic foci involved in mRNA metabolism. More importantly, depletion of hCaf1a/b or hCcr4a/b dramatically inhibits cell proliferation and tumorigenicity. Our results suggest that perturbating global RNA metabolism may provide a potential novel strategy for cancer treatment. Abstract Cancer cells generally have reprogrammed gene expression profiles to meet the requirements of survival, continuous division, and metastasis. An interesting question is whether the cancer cells will be affected by interfering their global RNA metabolism. In this research, we found that human Ccr4a/b (hCcr4a/b) and Caf1a/b (hCaf1a/b) deadenylases, the catalytic components of the Ccr4-Not complex, were dysregulated in several types of cancers including stomach adenocarcinoma. The impacts of the four deadenylases on cancer cell growth were studied by the establishment of four stable MKN28 cell lines with the knockdown of hCcr4a/b or hCaf1a/b or transient knockdown in several cell lines. Depletion of hCcr4a/b or hCaf1a/b significantly inhibited cell proliferation and tumorigenicity. Mechanistic studies indicated that the cells were arrested at the G2/M phase by knocking down hCaf1a, while arrested at the G0/G1 phase by depleting hCaf1b or hCcr4a/b. The four enzymes did not affect the levels of CDKs and cyclins but modulated the levels of CDK–cyclin inhibitors. We identified that hCcr4a/b, but not hCaf1a/b, targeted the p21 mRNA in the MKN28 cells. Furthermore, depletion of any one of the four deadenylases dramatically impaired processing-body formation in the MKN28 and HEK-293T cells. Our results highlight that perturbating global RNA metabolism may severely affect cancer cell proliferation, which provides a potential novel strategy for cancer treatment.
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影响因子：
3.7
作者：
Doidge R;Mittal S;Aslam A;Winkler GS
通讯作者：
Winkler GS
影响因子：
6.6
作者：
Cheng DD;Li J;Li SJ;Yang QC;Fan CY
通讯作者：
Fan CY
影响因子：
64.8
作者：
Lee, Yoonjin;Dominy, John E.;Choi, Yoon Jong;Jurczak, Michael;Tolliday, Nicola;Camporez, Joao Paulo;Chim, Helen;Lim, Ji-Hong;Ruan, Hai-Bin;Yang, Xiaoyong;Vazquez, Francisca;Sicinski, Piotr;Shulman, Gerald I.;Puigserver, Pere
通讯作者：
Puigserver, Pere
DOI：
10.1073/pnas.1212533110
发表时间：
2013-02-26
影响因子：
11.1
作者：
Devany, Emral;Zhang, Xiaokan;Kleiman, Frida Esther
通讯作者：
Kleiman, Frida Esther
影响因子：
3.3
作者：
Aslam, Akhmed;Mittal, Saloni;Winkler, G. Sebastiaan
通讯作者：
Winkler, G. Sebastiaan