Up-regulation of DNMT3b contributes to HOTAIRM1 silencing via DNA hypermethylation in cells transformed by long-term exposure to hydroquinone and workers exposed to benzene

Zhang, Haiqiao; Yuan, Qian; Pan, Zhijie; Ling, Xiaoxuan; Tan, Qiang; Wu, Ming‐Chi; Zheng, Dongyan; Xie, Peien; Xie, Daxiao; Liu, Linhua

doi:10.1016/j.toxlet.2019.12.028

Cited by 17 publications

(19 citation statements)

References 32 publications

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“…N6-methyladenosine (m6A) methylation mediated by METTL3 and METTL14 contributes to the increased stability of LNCAROD [ 44 ]. A recent study described that the DNA methyltransferase DNMT3b can reduce HOTAIRM1 expression in AML [ 45 ]. Thus, other possible regulatory mechanisms contributing to HOTAIRM1 expression in NPM1-mutated AML merit further exploration.…”

Section: Discussionmentioning

confidence: 99%

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

Jing

Jiang

et al. 2021

J Exp Clin Cancer Res

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Background Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1), which displays a distinct long noncoding RNA (lncRNA) expression profile, has been defined as a unique subgroup in the new classification of myeloid neoplasms. However, the biological roles of key lncRNAs in the development of NPM1-mutated AML are currently unclear. Here, we aimed to investigate the functional and mechanistic roles of the lncRNA HOTAIRM1 in NPM1-mutated AML. Methods The expression of HOTAIRM1 was analyzed with a public database and further determined by qRT-PCR in NPM1-mutated AML samples and cell lines. The cause of upregulated HOTAIRM1 expression was investigated by luciferase reporter, chromatin immunoprecipitation and ubiquitination assays. The functional role of HOTAIRM1 in autophagy and proliferation was evaluated using western blot analysis, immunofluorescence staining, a Cell Counting Kit-8 (CCK-8) assay, a 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, flow cytometric analyses and animal studies. The action mechanism of HOTAIRM1 was explored through RNA fluorescence in situ hybridization, RNA pulldown and RNA immunoprecipitation assays. Results HOTAIRM1 was highly expressed in NPM1-mutated AML. High HOTAIRM1 expression was induced in part by mutant NPM1 via KLF5-dependent transcriptional regulation. Importantly, HOTAIRM1 promoted autophagy and proliferation both in vitro and in vivo. Mechanistic investigations demonstrated that nuclear HOTAIRM1 promoted EGR1 degradation by serving as a scaffold to facilitate MDM2-EGR1 complex formation, while cytoplasmic HOTAIRM1 acted as a sponge for miR-152-3p to increase ULK3 expression. Conclusions Taken together, our findings identify two oncogenic regulatory axes in NPM1-mutated AML centered on HOTAIRM1: one involving EGR1 and MDM2 in the nucleus and the other involving the miR-152-3p/ULK3 axis in the cytoplasm. Our study indicates that HOTAIRM1 may be a promising therapeutic target for this distinct leukemia subtype.

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Section: Discussionmentioning

confidence: 99%

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

Jing

Jiang

et al. 2021

J Exp Clin Cancer Res

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“…Benzene has been classified as a group 1A carcinogen [ 25 ]. Findings from many studies support that workers exposed to benzene have higher incidence of hematological malignancies, primarily acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and myelodysplastic syndrome (MDS) [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. There is some limited evidence showing that benzene exposure has been causatively linked with increased risk of lung cancer [ 44 , 45 , 46 ], breast cancer (in animal model) [ 47 , 48 , 49 ], prostate cancer [ 50 ], kidney cancer [ 51 ], or bladder cancer [ 52 ].…”

Section: Carcinogenic Potential Of Chemicals Associated With Air Pollution From Gasolinementioning

confidence: 99%

“…Third, DNA strand breaks induced by benzene exposure may increase DNMT binding affinity at specific sites. Fourth, a significant decrease in mRNA levels of DNA methyltransferase (DNMT) 1, 3a, 3b and MBD2 was observed post exposure to benzene alone or BTX [ 19 , 248 ], particularly benzene-induced DNMT3b upregulation [ 32 ]. It is still largely unclear how benzene changes DNMT gene expression.…”

Section: Epigenetic Effects Associated With Carcinogenic Chemicals From Gasolinementioning

confidence: 99%

An Assessment on Ethanol-Blended Gasoline/Diesel Fuels on Cancer Risk and Mortality

Mueller

Dennison

Liu

2021

IJERPH

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Although cancer is traditionally considered a genetic disease, the epigenetic abnormalities, including DNA hypermethylation, histone deacetylation, and/or microRNA dysregulation, have been demonstrated as a hallmark of cancer. Compared with gene mutations, aberrant epigenetic changes occur more frequently, and cellular epigenome is more susceptible to change by environmental factors. Excess cancer risks are positively associated with exposure to occupational and environmental chemical carcinogens, including those from gasoline combustion exhausted in vehicles. Of note, previous studies proposed particulate matter index (PMI) as a measure for gasoline sooting tendency, and showed that, compared with the other molecules in gasoline, 1,2,4–Trimethylbenzene, 2–methylnaphthalene and toluene significantly contribute to PMI of the gasoline blends. Mechanistically, both epigenome and genome are important in carcinogenicity, and the genotoxicity of chemical agents has been thoroughly studied. However, less effort has been put into studying the epigenotoxicity. Moreover, as the blending of ethanol into gasoline substitutes for carcinogens, like benzene, toluene, xylene, butadiene, and polycyclic aromatic hydrocarbons, etc., a reduction of secondary aromatics has been achieved in the atmosphere. This may lead to diminished cancer initiation and progression through altered cellular epigenetic landscape. The present review summarizes the most important findings in the literature on the association between exposures to carcinogens from gasoline combustion, cancer epigenetics and the potential epigenetic impacts of biofuels.

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“…The DNMT3b knockout HQ-MT cells obtained using CRISPR/Cas9 system had promoter hypomethylation and high expression of HOTAIRM1. Long exposure to hydroquinone or benzene may increase DNMT3b expression and the promoter hypermethylation; the result is the silencing of HOTAIRM1 expression, a possible tumorsuppressor 29 .…”

Section: Combined Pathophysiological Mechanismsmentioning

confidence: 99%

The high-performance technology CRISPR/Cas9 improves knowledge and management of acute myeloid leukemia

Mihăilă¹,

Topircean²

2021

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Knowledge on acute myeloid leukemia pathogenesis and treatment has progressed recently, but not enough to provide ideal management. Improving the prognosis of acute myeloid leukemia patients depends on advances in molecular biology for the detection of new therapeutic targets and the production of effective drugs. The CRISPR/Cas9 technology allows gene insertions and deletions and it is the first step in investigating the function of their encoded proteins. Thus, new experimental models have been developed and progress has been made in understanding protein metabolism, antitumor activity, leukemic cell maintenance, differentiation, growth, apoptosis, and self-renewal, the combined pathogenetic mechanisms involved in leukemogenesis. The CRISPR/Cas9 system is used to understand drug resistance and find solutions to overcome it. The therapeutic progress achieved using the CRISPR/Cas9 system is remarkable. FST gene removal inhibited acute myeloid leukemia cell growth. Lysine acetyltransferase gene deletion contributed to decreased proliferation rate, increased apoptosis, and favored differentiation of acute myelid leukemia cells carrying MLL-X gene fusions. The removal of CD38 gene from NK cells decreased NK fratricidal cells contributing to increased efficacy of new CD38 CAR-NK cells to target leukemic blasts. BCL2 knockout has synergistic effects with FLT3 inhibitors. Exportin 1 knockout is synergistic with midostaurin treatment in acute myeloid leukemia with FLT3-ITD mutation. Using the results of CRISPR/Cas9 libraries and technology application will allow us to get closer to achieving the goal of curing acute myeloid leukemia in the coming decades.

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Up-regulation of DNMT3b contributes to HOTAIRM1 silencing via DNA hypermethylation in cells transformed by long-term exposure to hydroquinone and workers exposed to benzene

Cited by 17 publications

References 32 publications

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

Mutant NPM1-regulated lncRNA HOTAIRM1 promotes leukemia cell autophagy and proliferation by targeting EGR1 and ULK3

An Assessment on Ethanol-Blended Gasoline/Diesel Fuels on Cancer Risk and Mortality

The high-performance technology CRISPR/Cas9 improves knowledge and management of acute myeloid leukemia

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