Inhibition of UBE2N-dependent CDK6 protein degradation by miR-934 promotes human bladder cancer cell growth
Inhibition of UBE2N-dependent CDK6 protein degradation by miR-934 promotes human bladder cancer cell growth
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miR-934 抑制 UBE2N-依赖性 CDK6 蛋白降解可促进人膀胱癌细胞生长
DOI：
10.1096/fj.201900499rr
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发表时间：
2019-11-01
期刊：
影响因子：
4.8
通讯作者：
Huang, Haishan
中科院分区：
文献类型：
--
作者：
Yan, Huiying;Ren, Shuwei;Huang, Haishan
BC细胞生长相关效应物具有重要意义。细胞周期蛋白依赖性激酶（CDK）6是细胞周期相关蛋白CDK家族的成员，在癌细胞生长中起重要作用。CDK 6抑制剂已被批准用于治疗多种类型的癌症，这一事实就证明了这一点。然而，关于如何调节CDK 6在BC中表达的潜在分子机制仍不清楚。在本研究中，观察到miR-934在人BC和人BC细胞系中也高得多。结果还显示，miR-934抑制显著降低体外人BC细胞单层生长和体内异种移植肿瘤生长;结果伴随着CDK 6蛋白下调和G（0）-G（1）细胞周期停滞。此外，CDK 6的过表达逆转了miR-934诱导的BC细胞生长抑制。进一步的研究表明，miR-934与泛素结合酶2N（ube 2n）mRNA的3 '-UTR结合，下调UBE 2N蛋白表达;这反过来又减弱了CDK 6蛋白降解，导致CDK 6蛋白积累以及促进BC肿瘤生长。总的来说，这项研究不仅建立了一个新的调控轴的miR-934/UBE 2N的CDK 6，但也提供了数据表明，miR-934和UBE 2N可能是潜在的有希望的目标，针对BC的治疗策略。
BC cell growth-associated effectors is of great significance. Cyclin-dependent kinase (CDK)6 is a member of the CDK family of cell cycle-related proteins and plays an important role in cancer cell growth. This is borne out by the fact that a CDK6 inhibitor had been approved to treat several types of cancers. Nevertheless, underlying molecular mechanisms concerning how to regulate CDK6 expression in BC remains unclear. In the present study, it was observed that miR-934 was much higher in human BCs and human BC cell lines as well. The results also revealed that miR-934 inhibition dramatically decreased human BC cell monolayer growth in vitro and xenograft tumor growth in vivo; the outcomes were accompanied by CDK6 protein down-regulation and G(0)-G(1) cell cycle arrest. Moreover, overexpression of CDK6 reversed the inhibition of BC cell growth induced by miR-934. Further studies showed that miR-934 binds to a 3'-UTR of ubiquitin-conjugating enzyme 2N (ube2n) mRNA, down-regulated UBE2N protein expression; this, in turn, attenuated CDK6 protein degradation and led to CDK6 protein accumulation as well as the promotion of BC tumor growth. Collectively, this study not only establishes a novel regulatory axis of miR-934/UBE2N of CDK6 but also provides data suggesting that miR-934 and UBE2N may be potentially promising targets for therapeutic strategies against BC.