Benzene exposure is a risk factor of acute myeloid leukemia (AML), during such carcinogenesis long non-coding RNAs (lncRNAs) are important epigenetic regulators. HOTAIRM1 (HOXA transcript antisense RNA, myeloid-specific 1) plays an indispensable role in the development of AML. Hydroquinone (HQ) is one major metabolite of benzene and its ideal replacement in toxicology research. But the influence of benzene or HQ on HOTAIRM1 expression in AML associated pathway is still unclear. In the TK6 cells with short-term exposure to HQ (HQ-ST cells) or long term HQ exposure induced malignant transformed TK6 cells (HQ-MT cells), the relationship between DNMT3b and HOTAIRM1 was explored. Comparing to counterparts, HOTAIRM1 expression was increased firstly and then decreased in HQ-ST cells, and definitely decreased in HQ-MT cells; while the expression change tendency of DNMT3b was in contrast to that of HOTAIRM1. Moreover, the average HOTAIRM1 expression of 17 paired workers being exposed to benzene within 1.5 years was increased, but that of the remaining 92 paired workers with longer exposure time was decreased. Furthermore, in 5-AzaC (DNA methyltransferase inhibitor) or TSA (histone deacetylation inhibitor) treated HQ-MT cells, the expression of HOTAIRM1 was restored by reduced DNA promoter methylation levels. HQ-MT cells with DNMT3b knockout by CRISPR/Cas9 displayed the promoter hypomethylation and the increase of HOTAIRM1, also confirmed in benzene exposure workers. These suggest that long term exposure to HQ or benzene might induce the increase of DNMT3b expression and the promoter hypermethylation to silence the expression of HOTAIRM1, a possible tumor-suppressor in the AML associated carcinogenesis pathway.

中文翻译：

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在长期接触对苯二酚和接触苯的工人转化的细胞中，DNMT3b 的上调通过 DNA 高甲基化导致 HOTAIRM1 沉默


苯暴露是急性髓系白血病 (AML) 的危险因素，在这种致癌过程中，长非编码 RNA (lncRNA) 是重要的表观遗传调节因子。 HOTAIRM1（HOXA转录反义RNA，骨髓特异性1）在AML的发生发展中发挥着不可或缺的作用。对苯二酚（HQ）是苯的一种主要代谢物，也是毒理学研究中的理想替代品。但苯或HQ对AML相关通路中HOTAIRM1表达的影响仍不清楚。在短期暴露于HQ的TK6细胞（HQ-ST细胞）或长期暴露于HQ诱导的恶性转化TK6细胞（HQ-MT细胞）中，探讨了DNMT3b和HOTAIRM1之间的关系。与对照组相比，HQ-ST细胞中HOTAIRM1表达先升高后降低，HQ-MT细胞中HOTAIRM1表达明显降低；而DNMT3b的表达变化趋势与HOTAIRM1相反。此外，1.5年内接触苯的17对工人的平均HOTAIRM1表达量增加，但暴露时间较长的其余92对工人的平均HOTAIRM1表达量下降。此外，在 5-AzaC（DNA 甲基转移酶抑制剂）或 TSA（组蛋白脱乙酰化抑制剂）处理的 HQ-MT 细胞中，HOTAIRM1 的表达通过降低 DNA 启动子甲基化水平而恢复。通过 CRISPR/Cas9 敲除 DNMT3b 的 HQ-MT 细胞显示启动子低甲基化和 HOTAIRM1 增加，这也在苯接触工人中得到证实。这些表明，长期接触 HQ 或苯可能会诱导 DNMT3b 表达增加和启动子高甲基化，从而沉默 HOTAIRM1 的表达，HOTAIRM1 是 AML 相关致癌途径中可能的肿瘤抑制剂。