Depletion of the m1A writer TRMT6/TRMT61A reduces proliferation and resistance against cellular stress in bladder cancer.
Depletion of the m1A writer TRMT6/TRMT61A reduces proliferation and resistance against cellular stress in bladder cancer.
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m1A写入者TRMT6/TRMT61A的耗竭可降低膀胱癌的增殖和对细胞应激的抵抗。
DOI：
10.3389/fonc.2023.1334112
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发表时间：
2023
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
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作者：
膀胱癌（Bladder cancer，BLCA）是一种常见的恶性肿瘤，严重影响患者的生活质量，给社会带来巨大的经济负担。需要更好地了解肿瘤发生以改善临床结果。最近的证据将RNA修饰m1A及其调节蛋白TRMT 6/TRMT 61 A和ALKBH 3置于BLCA发病机制中。通过qRT-PCR和蛋白质印迹分析，在人BLCA细胞系和正常尿路上皮细胞系中检测TRMT 6/TRMT 61 A、ALKBH 1和ALKBH 3表达。进行Prestoblue细胞活力试剂、伤口愈合试验和基于活细胞成像的细胞置换分析，以评估该BLCA细胞系组的增殖、迁移和置换。在诱导细胞应激和用衣霉素激活未折叠蛋白反应（UPR）后评估细胞存活。此外，在两个BLCA细胞系（5637和HT 1197）中进行了siRNA介导的基因沉默，以研究TRMT 6/TRMT 61 A的生物学作用。异质形态，增殖，位移，衣霉素的敏感性，和表达水平的m1A调节剂之间的面板的细胞系检查观察。一般而言，与SV-HUC-1相比，BLCA细胞系中TRMT 61 A表达增加。TRMT 6/TRMT 61 A的耗尽降低了5637和HT 1197细胞系中的增殖能力。在TRMT 6/TRMT 61 A耗尽后，5637的平均细胞位移也减少。有趣的是，TRMT 6/TRMT 61 A缺失降低了5637中与UPR的ATF 6-分支相关的靶标的mRNA表达，但在HT 1197中没有。此外，TRMT 6/TRMT 61 A敲低后，在5637细胞中诱导细胞应激后的细胞存活受到损害，但在HT 1197细胞中没有。研究结果表明，TRMT 6/TRMT 61 A在BLCA中起致癌作用，并参与使BLCA细胞对细胞应激脱敏。进一步研究TRMT 6/TRMT 61 A表达的调控及其对细胞应激耐受的影响可能为未来BLCA治疗提供见解。
Bladder cancer (BLCA) is a common and deadly disease that results in a reduced quality of life for the patients and a significant economic burden on society. A better understanding of tumorigenesis is needed to improve clinical outcomes. Recent evidence places the RNA modification m1A and its regulatory proteins TRMT6/TRMT61A and ALKBH3 in BLCA pathogenesis. TRMT6/TRMT61A, ALKBH1, and ALKBH3 expression was examined in human BLCA cell lines and a normal urinary tract epithelium cell line through qRT-PCR and western blot analysis. Prestoblue Cell Viability Reagent, wound-healing assay, and live-cell imaging-based cell displacement analysis, were conducted to assess proliferation, migration, and displacement of this BLCA cell line panel. Cell survival was assessed after inducing cellular stress and activating the unfolded protein response (UPR) with tunicamycin. Moreover, siRNA-mediated gene silencing in two BLCA cell lines (5637 and HT1197) was conducted to investigate the biological roles of TRMT6/TRMT61A. Heterogeneous morphology, proliferation, displacement, tunicamycin sensitivity, and expression levels of m1A regulators were observed among the panel of cell lines examined. In general, TRMT61A expression was increased in BLCA cell lines when compared to SV-HUC-1. Depletion of TRMT6/TRMT61A reduced proliferation capacity in both 5637 and HT1197 cell lines. The average cell displacement of 5637 was also reduced upon TRMT6/TRMT61A depletion. Interestingly, TRMT6/TRMT61A depletion decreased mRNA expression of targets associated with the ATF6-branch of the UPR in 5637 but not in HT1197. Moreover, cell survival after induction of cellular stress was compromised after TRMT6/TRMT61A knockdown in 5637 but not in HT1197 cells. The findings suggest that TRMT6/TRMT61A plays an oncogenic role in BLCA and is involved in desensitizing BLCA cells against cellular stress. Further investigation into the regulation of TRMT6/TRMT61A expression and its impact on cellular stress tolerance may provide insights for future BLCA treatment.
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TRMT6/61a依赖性tRNA衍生片段的碱甲基化调节基因分解活性和膀胱癌中展开的蛋白质反应。
影响因子：
16.6
作者：
通讯作者：
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影响因子：
5.5
作者：
Nie Z;Chen M;Wen X;Gao Y;Huang D;Cao H;Peng Y;Guo N;Ni J;Zhang S
通讯作者：
Zhang S
影响因子：
8
作者：
Macari, F.;El-houfi, Y.;Joubert, D.
通讯作者：
Joubert, D.
影响因子：
16
作者：
Ougland, R;Zhang, CM;Falnes, PO
通讯作者：
Falnes, PO
DOI：
10.1038/s41568-020-00313-1
发表时间：
2021-02
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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