Role of N6-methyladenosine modification in cancer

Deng, Xiaolan; Su, Rui; Feng, Xuesong; Wei, Minjie; Chen, Jianjun

doi:10.1016/j.gde.2017.10.005

Cited by 182 publications

(168 citation statements)

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“…53,54 In particular, N 6methyladenosine (m 6 A) has been shown recently to play essential roles in various bioprocesses. [55][56][57] Moreover, m6A RNA methylation regulates tumorigenesis 58,59 and controls stem cell self-renewal and promotes cancer progression. 60,61 It indicates that the regulation of However, this action was abrogated by inhibiting miR6079 or increasing JMJD2A in miR24-2 overexpressing Hep3B cells.…”

Section: Discussionmentioning

confidence: 99%

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

Yang

Song

Meng

et al. 2020

J Cellular Molecular Medi

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Several microRNAs are associated with carcinogenesis and tumour progression. Herein, our observations suggest both miR24‐2 and Pim1 are up‐regulated in human liver cancers, and miR24‐2 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR24‐2 increases the expression of N6‐adenosine‐methyltransferase METTL3 and thereafter promotes the expression of miR6079 via RNA methylation modification. Furthermore, miR6079 targets JMJD2A and then increased the tri‐methylation of histone H3 on the ninth lysine (H3K9me3). Therefore, miR24‐2 inhibits JMJD2A by increasing miR6079 and then increases H3K9me3. Strikingly, miR24‐2 increases the expression of Pim1 dependent on H3K9me3 and METTL3. Notably, our findings suggest that miR24‐2 alters several related genes (pHistone H3, SUZ12, SUV39H1, Nanog, MEKK4, pTyr) and accelerates progression of liver cancer cells through Pim1 activation. In particular, Pim1 is required for the oncogenic action of miR24‐2 in liver cancer. This study elucidates a novel mechanism for miR24‐2 in liver cancer and suggests that miR24‐2 may be used as novel therapeutic targets of liver cancer.

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Section: Discussionmentioning

confidence: 99%

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

Yang

Song

Meng

et al. 2020

J Cellular Molecular Medi

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“…For example, HuR (11) and IGF2BPs (12) enhance the stabilization of the m 6 A-modified mRNA while YTHDF2 contributes to the decay of m 6 A-modified mRNA (13). m 6 A modification is linked to a variety of biological processes that are important for cancer development and progression (14). Here, we show that m 6 A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the canonical Wnt/b-catenin signaling in BRCA1/2-mutated ovarian cancer cells.…”

Section: Introductionmentioning

confidence: 99%

N6-Methylation of Adenosine of FZD10 mRNA Contributes to PARP Inhibitor Resistance

et al. 2019

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Despite the high initial response rates to PARP inhibitors (PARPi) in BRCA-mutated epithelial ovarian cancers (EOC), PARPi resistance remains a major challenge. Chemical modifications of RNAs have emerged as a new layer of epigenetic gene regulation. N 6 -methyladenosine (m 6 A) is the most abundant chemical modification of mRNA, yet the role of m 6 A modification in PARPi resistance has not previously been explored. Here, we show that m 6 A modification of FZD10 mRNA contributes to PARPi resistance by upregulating the Wnt/b-catenin pathway in BRCA-mutated EOC cells. Global m 6 A profile revealed a significant increase in m 6 A modification in FZD10 mRNA, which correlated with increased FZD10 mRNA stability and an upregulation of the Wnt/b-catenin pathway. Depletion of FZD10 or inhibition of the Wnt/b-catenin sensitizes resistant cells to PARPi. Mechanistically, downregulation of m 6 A demethylases FTO and ALKBH5 was suffi-cient to increase FZD10 mRNA m 6 A modification and reduce PARPi sensitivity, which correlated with an increase in homologous recombination activity. Moreover, combined inhibition of PARP and Wnt/b-catenin showed synergistic suppression of PARPi-resistant cells in vitro and in vivo in a xenograft EOC mouse model. Overall, our results show that m 6 A contributes to PARPi resistance in BRCA-deficient EOC cells by upregulating the Wnt/b-catenin pathway via stabilization of FZD10. They also suggest that inhibition of the Wnt/b-catenin pathway represents a potential strategy to overcome PARPi resistance.Significance: These findings elucidate a novel regulatory mechanism of PARPi resistance in EOC by showing that m 6 A modification of FZD10 mRNA contributes to PARPi resistance in BRCA-deficient EOC cells via upregulation of Wnt/b-catenin pathway.

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“…27 N 6 -methyladenosine (m 6 A) is an abundant reversible epitranscriptomic modification 28 found in coding and non-coding RNAs [1][2][3][4]. It plays important roles in RNA metabolism 29 [5][6][7][8] and is implicated in a growing number of cellular processes [9][10][11][12][13][14][15]. m 6 A has also 30 been found in viral RNAs where it is proposed to modulate host-pathogen interactions 31 [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

m6A minimally impacts the structure, dynamics, and Rev ARM binding properties of HIV-1 RRE stem IIB

Chu

Liu

Plangger

et al. 2019

Preprint

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13 N 6 -methyladenosine (m 6 A) is a ubiquitous RNA post-transcriptional modification found 14 in coding as well as non-coding RNAs. m 6 A has also been found in viral RNAs where it 15 is proposed to modulate host-pathogen interactions. Two m 6 A sites have been reported 16 in the HIV-1 Rev response element (RRE) stem IIB, one of which was shown to 17 enhance binding to the viral protein Rev and viral RNA export. However, because these 18 m 6 A sites have not been observed in other studies mapping m 6 A in HIV-1 RNA, their 19 significance remains to be firmly established. Here, using optical melting experiments, 20 NMR spectroscopy, and in vitro binding assays, we show that m 6 A minimally impacts 21 the stability, structure, and dynamics of RRE stem IIB as well as its binding affinity to 22 the Rev arginine-rich-motif (ARM). Our results indicate that if present in stem IIB, m 6 A 23 is unlikely to modulate RRE-Rev interaction by altering the conformational properties of 24 the RNA. Our results add to a growing view that the impact of m 6 A on RNA depends on 25 sequence context and Mg 2+ . 26 Introduction27 N 6 -methyladenosine (m 6 A) is an abundant reversible epitranscriptomic modification 28 found in coding and non-coding RNAs [1][2][3][4]. It plays important roles in RNA metabolism 29 [5][6][7][8] and is implicated in a growing number of cellular processes [9][10][11][12][13][14][15]. m 6 A has also 30 been found in viral RNAs where it is proposed to modulate host-pathogen interactions 31 [16][17][18][19]. 32A number of studies have reported m 6 A in the HIV-1 RNA genome [18,20,21].33 One study examining HIV-1 infected human T cells [20] reported two m 6 A sites (A68 34 and A62, Fig 1) in the Rev response element (RRE) stem IIB. RRE is a ~350 nt cis-35 acting RNA element that is recognized by viral Rev protein to promote the export of 36 unspliced or partially spliced viral RNA to express the structural proteins required for 37 viral replication [22][23][24]. The two m 6 A sites were found in stem IIB (RREIIB), which is 38 the primary binding site for Rev [23,[25][26][27]. Knocking down the methyltransferase 39 complex (METTL3/METTL14) was shown to suppress Rev-RRE mediated RNA export 40 and viral replication, and point substitution mutation of one of the two highly conserved 41 adenines (A68) strongly suppressed viral replication (> 90%) [20]. It was proposed [20] 42 that the methyl group of m 6 A68 may interact with Rev protein to stabilize Rev-RRE 43 binding, and/or that m 6 A68 may alter the conformational properties of stem IIB to 44 facilitate Rev recognition. Another different study employing distinct cell lines and 45 mapping methods did not observe these m 6 A sites on RREIIB [21] while a third study 46 found m 6 A in RRE but did not identify the specific site [18]. 47Here, we asked whether methylation of RREIIB with m 6 A leads to changes in its 48 conformational and Rev arginine rich motif (ARM) binding properties. We were driven 4 49 to test this hypothesis because our recent studies showed that t...

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Role of N6-methyladenosine modification in cancer

Cited by 182 publications

References 57 publications

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

N6-Methylation of Adenosine of FZD10 mRNA Contributes to PARP Inhibitor Resistance

m6A minimally impacts the structure, dynamics, and Rev ARM binding properties of HIV-1 RRE stem IIB

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