Lung cancer cells expressing a shortened CDK16 3'UTR escape senescence through impaired miR-485-5p targeting.
Lung cancer cells expressing a shortened CDK16 3'UTR escape senescence through impaired miR-485-5p targeting.
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DOI：
10.1002/1878-0261.13125
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发表时间：
2022-03
影响因子：
6.6
通讯作者：
Ni T
中科院分区：
文献类型：
--
作者：
Jia Q;Xie B;Zhao Z;Huang L;Wei G;Ni T
诱导癌细胞衰老是一种新兴的癌症治疗策略。编码细胞周期蛋白依赖性激酶（CDK）的基因的失调和突变与多种人类癌症有关。然而，CDK是否可以诱导癌细胞衰老仍知之甚少。我们观察到 CDK16 在包括肺癌在内的多种癌症类型中表达较高，而各种复制性衰老模型则表现出较低的 CDK16 表达。 CDK16 敲低导致肺癌细胞系出现衰老相关表型。有趣的是，CDK16 3' UTR 在癌症中缩短，在衰老模型中延长，这是由替代多腺苷酸化 (APA) 调节的。较长的 3'UTR [使用远端 PolyA (pA) 位点] 产生的蛋白质比较短的 3'UTR（使用近端 pA 位点）少。由于 microRNA (miRNA) 通常与靶基因的 3'UTR 结合以抑制其表达，因此我们研究了针对缩短和较长 3'UTR 之间区域的 miRNA 是否是导致表达减少的原因。我们发现 miR-485-5p 靶向远端和近端 pA 位点之间的 3'UTR，并通过减少较长 CDK16 转录物的蛋白质产生来引起衰老相关表型。值得注意的是，CDK16敲低导致MYC原癌基因、bHLH转录因子（MYC）和CD274分子（PD-L1）的表达减少，从而增强衰老癌细胞的肿瘤抑制作用。本研究发现CDK16的表达受到APA和miR-485-5p的调控，是肺癌早衰治疗的潜在靶点。本研究发现非小细胞肺癌（NSCLC）和衰老细胞在 CDK16 表达和替代多腺苷酸化（APA）使用方面具有相反的趋势。 NSCLC 细胞中 APA 介导的 CDK16 3' UTR 缩短逃避了 miR-485-5p 结合，导致 CDK16 表达增加。此外，CDK16抑制和miR-485-5p过表达均可诱导肺癌细胞衰老，从而促进肿瘤抑制作用。
Inducing senescence in cancer cells is an emerging strategy for cancer therapy. The dysregulation and mutation of genes encoding cyclin‐dependent kinases (CDKs) have been implicated in various human cancers. However, whether CDK can induce cancer cell senescence remains poorly understood. We observed that CDK16 expression was high in multiple cancer types, including lung cancer, whereas various replicative senescence models displayed low CDK16 expression. CDK16 knockdown caused senescence‐associated phenotypes in lung cancer cell lines. Interestingly, the CDK16 3′ UTR was shortened in cancer and lengthened in senescence models, which was regulated by alternative polyadenylation (APA). The longer 3′UTR [using the distal polyA (pA) site] generated less protein than the shorter one (using the proximal pA site). Since microRNAs (miRNAs) usually bind to the 3′UTR of target genes to suppress their expression, we investigated whether miRNAs targeting the region between the shortened and longer 3′UTR are responsible for the reduced expression. We found that miR‐485‐5p targeted the 3′UTR between the distal and proximal pA site and caused senescence‐associated phenotypes by reducing protein production from the longer CDK16 transcript. Of note, CDK16 knockdown led to a reduced expression of MYC proto‐oncogene, bHLH transcription factor (MYC) and CD274 molecule (PD‐L1), which in turn enhanced the tumor‐suppressive effects of senescent cancer cells. The present study discovered that CDK16, whose expression is under the regulation of APA and miR‐485‐5p, is a potential target for prosenescence therapy for lung cancer. The present study discovers that non‐small cell lung cancer (NSCLC) and senescent cells have opposite trends in CDK16 expression and alternative polyadenylation (APA) usage. APA‐mediated 3′ UTR shortening of CDK16 in NSCLC cells evades miR‐485‐5p binding, resulting in increased CDK16 expression. Moreover, both CDK16 inhibition and miR‐485‐5p overexpression can induce senescence of lung cancer cells and thus promote tumor‐suppressive effects.
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DOI：
10.3322/caac.21244
发表时间：
2014-09
期刊：
CA: a cancer journal for clinicians
影响因子：
--
作者：
Berindan-Neagoe I;Monroig Pdel C;Pasculli B;Calin GA
通讯作者：
Calin GA
DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
影响因子：
50.3
作者：
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通讯作者：
Sicinski P
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
64.8
作者：
Berkovits BD;Mayr C
通讯作者：
Mayr C