Journal
TOXICOLOGY LETTERS
Volume 322, Issue -, Pages 12-19Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2019.12.028
Keywords
Benzene; Hydroquinone; HOTAIRM1; DNMT3b; DNA methylation
Categories
Funding
- National Natural Science Foundation of China [81202231]
- Natural Science Foundation of Guangdong Province [2018A0303130240]
- Project for Creative Talent of Guangdong Education Department [2014KQNCX102]
- Scientific Research Funding of Guangdong Medical University [B2017021]
- Medical Scientific Research Funding of Guangdong Province, China [A2018225]
- China Scholar Council [201708440542]
- Science and Technology Program of Guangdong Bureau of Science and Technology, China [2013B021800069]
- College Students Innovation and Entrepreneurship Training Program from Guangdong Medical University [2016ZZDG004, GDMU2017025, 201810571025]
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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.
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