HNRNPAl-mediated 3′ UTR length changes of HN1 contributes to cancer- and senescence-associated phenotypes
HNRNPAl-mediated 3′ UTR length changes of HN1 contributes to cancer- and senescence-associated phenotypes
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HNRNPA1 介导的 HN1 3' UTR 长度变化有助于癌症和衰老相关表型。
DOI：
10.18632/aging.102060
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发表时间：
2019-07-15
期刊：
影响因子：
5.2
通讯作者：
Ni, Ting
中科院分区：
文献类型：
--
作者：
Jia, Qi;Nie, Hongbo;Ni, Ting
细胞衰老被认为是肿瘤抑制的一种机制。研究细胞衰老过程中不同水平的基因表达调控将为癌症治疗提供线索。选择性多腺苷酸化 (APA) 通过改变 3' 非翻译区 (3' UTR) 来调节基因表达，并在多种生物过程中发挥重要作用。然而，特定基因的 APA 是否在癌症和衰老中均发挥作用仍不清楚。在这里，我们发现 HN1（或 JPT1）的 3' UTR 在癌症中表现出缩短，在衰老中表现出延长，分别与其在癌细胞中的高表达和在衰老细胞中的低表达密切相关。具有较长 3' UTR 的 HN1 转录本稳定性较差，产生的蛋白质较少。 HN1 的下调会在正常细胞和癌细胞中诱导衰老相关表型。 HN1 表达较高的患者在各种癌症中的生存率较低。有趣的是，下调剪接因子 HNRNPA1 会诱导 HN1 的 3' UTR 延长和衰老相关表型，这可以通过过表达 HN1 来部分逆转。我们共同首次揭示了 HNRNPA1 介导的 HN1 APA 有助于癌症和衰老相关表型。鉴于衰老是一种癌症预防机制，我们的发现表明 HNRNPA1-HN1 轴是癌症治疗的潜在靶点。
Cellular senescence has been regarded as a mechanism of tumor suppression. Studying the regulation of gene expression at various levels in cell senescence will shed light on cancer therapy. Alternative polyadenylation (APA) regulates gene expression by altering 3' untranslated regions (3' UTR) and plays important roles in diverse biological processes. However, whether APA of a specific gene functions in both cancer and senescence remains unclear. Here, we discovered that 3' UTR of HN1 (or JPT1) showed shortening in cancers and lengthening in senescence, correlated well with its high expression in cancer cells and low expression in senescent cells, respectively. HN1 transcripts with longer 3' UTR were less stable and produced less protein. Down-regulation of HN1 induced senescence-associated phenotypes in both normal and cancer cells. Patients with higher HN1 expression had lower survival rates in various carcinomas. Interestingly, down-regulating the splicing factor HNRNPA1 induced 3' UTR lengthening of HN1 and senescence-associated phenotypes, which could be partially reversed by overexpressing HN1. Together, we revealed for the first time that HNRNPA1-mediated APA of HN1 contributed to cancer- and senescence-related phenotypes. Given senescence is a cancer prevention mechanism, our discovery indicates the HNRNPA1-HN1 axis as a potential target for cancer treatment.