SIRT1 Regulates N6‐Methyladenosine RNA Modification in Hepatocarcinogenesis by Inducing RANBP2‐Dependent FTO SUMOylation

Liu, Xiaoming; Liu, Jianye; Xiao, Wen; Zeng, Qinghai; Bo, Hao; Zhu, Yuxing; Gong, Lian; He, Dong; Xing, Xiaowei; Li, Ruhong; Zhou, Ming; Wang, Xiong; Zhou, Yanhong; Zhou, Jianda; Li, Xiaohui; Guo, Fei; Xu, Canxia; Chen, Xiong; Wang, Xiaoyan; Wang, Fen; Wang, Qiang; Cao, Ke

doi:10.1002/hep.31222

Cited by 111 publications

(87 citation statements)

References 39 publications

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“…Those genes which were consistently validated in all three HCC cell lines were subject to further studies; h Protein level of LYPD1 was measured in ALKBH5-silenced Huh7 and MHCC97H cells or ALKBH5-overexpressing HCCLM3 cells the growth and invasion of HCC cells via diverse mechanisms [16,17,19]. And two studies have reported ambiguous results about FTO, which may serve as either an oncogene or a tumor suppressor in HCC [21,22]. Meanwhile, our preliminary experiments also found the controversial effects of FTO on proliferation abilities in different HCC cells (Additional file 9: Figure S5a-k).…”

Section: Discussionmentioning

confidence: 99%

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ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1

et al. 2020

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Background: N6-methyladenosine (m 6 A) modification is an emerging layer of epigenetic regulation which is widely implicated in the tumorigenicity of hepatocellular carcinoma (HCC), offering a novel perspective for investigating molecular pathogenesis of this disease. The role of AlkB homolog 5 (ALKBH5), one of the m 6 A demethylases, has not been fully explored in HCC. Here we clarify the biological profile and potential mechanisms of ALKBH5 in HCC. Methods: Expression of ALKBH5 and its correlation with clinicopathological characteristics of HCC were evaluated using tissue microarrays and online datasets. And biological effects of ALKBH5 in HCC were determined in vitro and in vivo. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq), and following m 6 A dot blot, MeRIP-qPCR, RIP-qPCR or dual luciferase reporter assays were employed to screen and validate the candidate targets of ALKBH5. Results: We demonstrated that ALKBH5 was down-regulated in HCC, and decreased ALKBH5 expression was an independent prognostic factor of worse survival in HCC patients. Functionally, ALKBH5 suppressed the proliferation and invasion capabilities of HCC cells in vitro and in vivo. Mechanistically, ALKBH5-mediated m 6 A demethylation led to a post-transcriptional inhibition of LY6/PLAUR Domain Containing 1 (LYPD1), which could be recognized and stabilized by the m 6 A effector IGF2BP1. In addition, we identified that LYPD1 induced oncogenic behaviors of tumors in contrast to ALKBH5. Dysregulation of ALKBH5/LYPD1 axis impelled the progression of HCC. Conclusion: Our study reveals that ALKBH5, characterized as a tumor suppressor, attenuates the expression of LYPD1 via an m 6 A-dependent manner in HCC cells. Our findings enrich the landscape of m 6 A-modulated tumor malignancy, and provide new insights into potential biomarkers and therapeutic targets of HCC treatment.

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Section: Discussionmentioning

confidence: 99%

“…Li et al illustrate that FTO facilitates the tumorigenesis of HCC via modulating PKM2 demethylation [21]. However, a most recent study delineates that FTO, which is regulated by SIRT1-induced SUMOylation, functions as a tumor suppressor in HCC [22]. These outcomes underscore the complexity of m 6 Amediated effects in HCC.…”

Section: Introductionmentioning

confidence: 99%

ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1

et al. 2020

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“…This, accompanied by an elevated level and redistribution of METTL3 expression in AD hippocampal tissue, likely represents abnormal misfolding and/or aggregation of METTL3, perhaps resembling the frequent aggregation of RNA-binding proteins in neurodegenerative disorders (Arai et al, 2009;Conlon and Manley, 2017). Given that several m6A regulatory proteins are subjected to post-translational ubiquitination and SUMOylation (Zhang et al, 2015;Tai et al, 2017;Du et al, 2018;Zhu et al, 2018;Liu et al, 2020;Xu et al, 2020), it is conceivable that dysregulation of the ubiquitin-proteasome system may contribute to the aggregation of METTL3 in AD (Ihara et al, 2012;Zheng et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer’s Disease

Huang

Camats-Perna

Medeiros

et al. 2020

eNeuro

102

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Cognitive impairment in Alzheimer's disease (AD) is associated with dysregulation of the RNA and protein expression profiles in the brain. Recent studies have highlighted the importance of RNA post-transcriptional regulation (epitranscriptomics) in higher order brain functions. Specifically, N6-methyladenosine (m6A), which controls RNA stability, splicing, translation and trafficking, plays an important role in learning and memory. This raises the question of whether m6A signaling is perturbed in AD. To address this, we investigated the expression profile of known m6A-regulatory genes using a public RNA-seq dataset and identified a subset of genes which were significantly dysregulated in the human AD brain. Among these, genes encoding the m6A methyltransferase, METTL3, and a member of the m6A methyltransferase complex (MACOM), RBM15B, were downregulated and upregulated in the hippocampus, respectively. These findings were validated at the protein level using an independent cohort of postmortem human brain samples. Unexpectedly, we observed an accumulation of methyltransferase-like 3 (METTL3), but not RBM15B, in the insoluble fractions, which positively correlated with the levels of insoluble Tau protein in the postmortem human AD samples. Aberrant expression and distribution of METTL3 in the hippocampus of the AD brain may therefore represent an epitranscriptomic mechanism underlying the altered gene expression patterns associated with disease pathogenesis.

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“…Low expression of METTL14 is associated with tumor differentiation, clinical stage, and microvascular invasion [48]. Low expression of ALKBH5 or FTO predicts an unfavorable marker in lung cancer and HCC [107,108]. IGF2BP2 is considered as a prognostic marker in pancreatic cancer, esophagogastric junction adenocarcinoma and CRC [60,109,110].…”

Section: A Regulators Are Regulated By Ncrnas In Cancermentioning

confidence: 99%

Novel insights into the interplay between m6A modification and noncoding RNAs in cancer

et al. 2020

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N6-methyladenosine (m 6 A) is one of the most common RNA modifications in eukaryotes, mainly in messenger RNA (mRNA). Increasing evidence shows that m 6 A methylation modification acts an essential role in various physiological and pathological bioprocesses. Noncoding RNAs (ncRNAs), including miRNAs, lncRNAs and circRNAs, are known to participate in regulating cell differentiation, angiogenesis, immune response, inflammatory response and carcinogenesis. m 6 A regulators, such as METTL3, ALKBH5 and IGF2BP1 have been reported to execute a m 6 Adependent modification of ncRNAs involved in carcinogenesis. Meanwhile, ncRNAs can target or modulate m 6 A regulators to influence cancer development. In this review, we provide an insight into the interplay between m 6 A modification and ncRNAs in cancer.

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SIRT1 Regulates N6‐Methyladenosine RNA Modification in Hepatocarcinogenesis by Inducing RANBP2‐Dependent FTO SUMOylation

Cited by 111 publications

References 39 publications

ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1

ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1

Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer’s Disease

Novel insights into the interplay between m6A modification and noncoding RNAs in cancer

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