EZH2 targeting to improve the sensitivity of acquired radio-resistance bladder cancer cells.
EZH2 targeting to improve the sensitivity of acquired radio-resistance bladder cancer cells.
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EZH2靶向提高获得性放射抗性膀胱癌细胞的敏感性
DOI：
10.1016/j.tranon.2021.101316
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发表时间：
2022-03
影响因子：
5
通讯作者：
Kong Z
中科院分区：
文献类型：
--
作者：
Zhang X;Ma X;Wang Q;Kong Z
分次照射丰富了BCA细胞的干细胞样特性，增加了EZH2的表达。EZH2基因的下调降低了BCA细胞的辐射抗性表型，降低了微球的形成和DNA修复能力。EZH2的下调影响了BCA细胞的自噬通量稳定性。下调EZH2基因可抑制体内ARR细胞的生长。在膀胱癌(BCA)的众多治疗方法中，放射治疗是一种保存膀胱的有效方法。然而，随着照射频率的增加，肿瘤细胞出现获得性放射抵抗(ARR)，并失去对放射治疗的敏感性。为了探讨ARR的分子机制，本研究以BCA细胞系5637和T24为研究对象，通过2Gy射线照射30次获得了相应的ARR细胞株5637R和T24R。与亲本细胞相比，ARR细胞显著增强了干细胞样表型，强大的DNA损伤修复能力，并上调了Zust Homolog 2(EZH2)的表达。与未经处理的细胞相比，亲本细胞和ARR细胞的微球形成能力和DNA损伤修复能力均降低，但细胞放射敏感性和细胞内自噬能力增强。在亲本细胞中，下调EZH2的表达导致Lc3和p62的表达增加，而在ARR细胞中，EZH2的表达降低时，只有Lc3的表达增加。另一方面，UNC1999处理导致所有细胞中LC3B和P62的表达增加，提示siEZH2和UN1999通过不同的机制影响ARR细胞的自噬。体内实验表明，UNC1999可显著增强T24R细胞对IR的敏感性，下调EZH2的表达可显著抑制肿瘤生长。结合生物信息学数据分析，我们推测EZH2是联系BCA诊断、放疗和预后的重要生物分子。EZH2靶向治疗可能是克服BCA ARR的有效方法，值得深入研究。
Fractionated irradiation enriched stem cell-like characteristics and increased EZH2 expression of BCa cells. Down-regulation of EZH2 reduced the radio-resistance phenotype and decreased the microsphere formation and DNA repair abilities of BCa cells. Down-regulation of EZH2 affected the autophagic-flux stability of BCa cells. Down-regulation of EZH2 inhibited ARR cells growth in vivo. Among the many treatments for Bladder cancer (BCa) patients, radiotherapy is an effective way to preserve the bladder. However, as the frequency of irradiation increases, the tumor cells appear "acquired radio-resistance" (ARR) and loss the sensitivity to radiotherapy. To explore the molecular mechanism of ARR, two BCa cell lines, 5637 and T24, were enrolled here and their ARR counterparts, 5637R and T24R, were obtained by exposure to γ-ray of 2 Gy for 30 times. Compared to parental cells, ARR cells have significantly enhanced stem cell-like phenotype, robust DNA damage repair capabilities and elevated expression of zeste homolog 2 (EZH2). Decreasing EZH2 expression, both parental and ARR cells exhibited reduced abilities of forming microsphere and repairing DNA damage, but enhanced cells radio-sensitivity and intracellular autophagy compared to untreated cells. Down-regulation the expression of EZH2 induced an increasing of both LC3 and P62 in parental cells, while in ARR cells, only LC3 increased upon EZH2 reduction. On the other hand, UNC1999 treatment caused the increasing of LC3B and P62 in all cells, suggested that siEZH2 and UNC1999 affect ARR cells autophagy through different mechanisms. In vivo study showed that pre-treated with UNC1999 greatly enhanced T24R cells sensitivity to IR, and knocking down the expression of EZH2 significantly suppressed the tumor growth. Combined with bioinformatics data analysis, we speculate that EZH2 is an important biomolecule linking the diagnosis, radiotherapy and prognosis of BCa. EZH2 targeted therapy may be an effective way to overcome ARR of BCa, and is worthy of in-depth study.
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