A PolH transcript with a short 3'UTR enhances PolH expression and mediates cisplatin resistance.
A PolH transcript with a short 3'UTR enhances PolH expression and mediates cisplatin resistance.
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DOI：
10.1158/0008-5472.can-18-3928
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发表时间：
2019-05
期刊：
影响因子：
11.2
通讯作者：
Jin Zhang;Wenqiang Sun;Cong Ren;Xiangmudong Kong;Wensheng Yan;Xinbin Chen
中科院分区：
文献类型：
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作者：
Jin Zhang;Wenqiang Sun;Cong Ren;Xiangmudong Kong;Wensheng Yan;Xinbin Chen
铂类抗癌药物被广泛用作非小细胞肺癌（NSCLC）和膀胱癌等癌症的一线治疗。然而，这些药物的疗效是有限的，由于内在或获得性耐药性。DNA聚合酶eta（PolH）属于DNA聚合酶的Y-家族并且介导DNA跨损伤合成，这是DNA损伤耐受的主要机制。在这里，我们发现高水平的PolH与肺癌和膀胱癌的顺铂耐药有关。PolH的缺失显著减弱了顺铂敏感和耐药肺癌细胞对顺铂的耐药性。由于存在多个多聚腺苷酸化位点，交替多聚腺苷酸化（阿帕）产生三种主要的PolH转录物，其具有不同长度的3 '非翻译区（3' UTR）（427-/2516-/6245-nt）。具有427-nt 3 'UTR的短PolH转录物负责PolH在各种顺铂耐药的肺癌和膀胱癌细胞系中的高表达，并且短PolH转录物的缺失显著地使癌细胞对顺铂治疗敏感。此外，我们发现miR 619选择性地抑制具有6245-nt 3 'UTR的长PolH转录物产生PolH蛋白的能力以及随后的PolH依赖性细胞生长。总之，我们的数据表明，PolH的表达是由阿帕控制，阿帕产生的短PolH转录本可以逃脱miR 619介导的抑制，并赋予PolH介导的顺铂耐药性。
Platinum-based anticancer drugs are widely used as a frontline therapy for cancers such as non-small-cell lung carcinoma (NSCLC) and bladder cancer. However, the efficacy of these drugs is limited due to intrinsic or acquired resistance. DNA polymerase eta (PolH) belongs to the Y-family of DNA polymerases and mediates DNA translesion synthesis, a major mechanism for DNA damage tolerance. Here we show that high levels of PolH are associated with cisplatin resistance in lung and bladder cancer. Loss of PolH markedly attenuated cisplatin resistance in both cisplatin-sensitive and cisplatin-resistant lung cancer cells. Due to the presence of multiple polyadenylation sites, alternative polyadenylation (APA) produced three major PolH transcripts with various lengths of 3'untranslated region (3'UTR) (427-/2516-/6245-nt). The short PolH transcript with 427-nt 3'UTR was responsible for high expression of PolH in various cisplatin-resistant lung and bladder cancer cell lines, and loss of the short PolH transcript significantly sensitized cancer cells to cisplatin treatment. Moreover, we found that miR619 selectively inhibited the ability of the long PolH transcript with 6245-nt 3'UTR to produce PolH protein and subsequently, PolH-dependent cell growth. Together, our data suggest that PolH expression is controlled by APA and that the short PolH transcript produced by APA can escape miR619-mediated repression and confer PolH-mediated cisplatin resistance.