Persistent phosphorylation at specific H3 serine residues involved in chemical carcinogen‐induced cell transformation
Persistent phosphorylation at specific H3 serine residues involved in chemical carcinogen‐induced cell transformation
复制标题
DOI：
10.1002/mc.22605
复制
发表时间：
2017-01
影响因子：
4.6
通讯作者：
Xiaonian Zhu;Daochuan Li;Zhengbao Zhang;Wei Zhu;Wen-xue Li;Jian Zhao;X. Xing;Zhini He;Shan Wang
中科院分区：
文献类型：
--
作者：
Xiaonian Zhu;Daochuan Li;Zhengbao Zhang;Wei Zhu;Wen-xue Li;Jian Zhao;X. Xing;Zhini He;Shan Wang
在化学致癌过程中识别异常的组蛋白H3磷酸化将有助于更好地理解组蛋白修饰在癌症发生中的重要作用。为了探讨H3异常磷酸化是否在化学致癌中起作用，我们检测了化学致癌物诱导的转化细胞和人类癌症中不同残基H3磷酸化的动态变化。我们发现，在黄曲霉毒素B1转化的肝细胞L02细胞(L02RT-AFB1)、苯并(A)芘转化的HBE细胞(HBERT-bap)和焦炉排放物转化的HBE细胞(HBERT-CoE)中，组蛋白H3在Ser10(p-H3S10)和Ser28(p-H3S28)的磷酸化水平分别上调了1.5-4.8倍和2.1-4.3倍。组蛋白H3突变体(H3S10A或H3S28A)在L02细胞中的异位表达导致了免疫缺陷小鼠锚定非依赖性细胞生长和肿瘤形成的抑制。此外，70.6%(24/34)的肝细胞癌和70.0%(21/30)的原发性肺癌p-H3S10表达增强。值得注意的是，我们发现携带突变体H3S10A或H3S28A的H3的表达赋予细胞保持更密集的染色质的能力，并抵抗DNA损伤的诱导和致癌物诱导的细胞转化。特别是，我们发现，在AFB1处理后，突变株H3S10A的引入取消了p-H3S10与DNA修复基因启动子PARP1和MLH1的结合。此外，我们还发现PP2A负责p-H3S10的去磷酸化。综上所述，这些结果揭示了持续的H3S10或H3S28磷酸化通过调节DNA损伤反应(DDR)基因的转录在化学致癌中的关键作用。
Identification of aberrant histone H3 phosphorylation during chemical carcinogenesis will lead to a better understanding of the substantial roles of histone modifications in cancer development. To explore whether aberrant H3 phosphorylation contributes to chemical carcinogenesis, we examined the dynamic changes of H3 phosphorylation at various residues in chemical carcinogen‐induced transformed human cells and human cancers. We found that histone H3 phosphorylation at Ser10 (p‐H3S10) and Ser28 (p‐H3S28) was upregulated by 1.5‐4.8 folds and 2.1‐4.3 folds, respectively in aflatoxin B1‐transformed hepatocytes L02 cells (L02RT‐AFB1), benzo(a)pyrene‐transformed HBE cells (HBERT‐BaP), and coke oven emissions‐transformed HBE cells (HBERT‐COE). The ectopic expression of histone H3 mutant (H3S10A or H3S28A) in L02 cells led to the suppression of an anchorage‐independent cell growth as well as tumor formation in immunodeficient mice. In addition, an enhanced p‐H3S10 was found in 70.6% (24/34) of hepatocellular carcinoma (HCC), and 70.0% (21/30) of primary lung cancer, respectively. Notably, we found that expression of H3 carrying a mutant H3S10A or H3S28A conferred to cells the ability to maintain a denser chromatin and resistance to induction of DNA damage and carcinogen‐induced cell transformation. Particularly, we showed that introduction of a mutant H3S10A abolished the bindings of p‐H3S10 to the promoter of DNA repair genes, PARP1 and MLH1 upon AFB1 treatment. Furthermore, we revealed that PP2A was responsible for dephosphorylation of p‐H3S10. Taken together, these results reveal a key role of persistent H3S10 or H3S28 phosphorylation in chemical carcinogenesis through regulating gene transcription of DNA damage response (DDR) genes.