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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-08-10

AUTHORS

Yunhao Chen, Yanchun Zhao, Junru Chen, Chuanhui Peng, Yanpeng Zhang, Rongliang Tong, Qiyang Cheng, Beng Yang, Xiaode Feng, Yuejie Lu, Haiyang Xie, Lin Zhou, Jian Wu, Shusen Zheng

ABSTRACT

BackgroundN6-methyladenosine (m6A) 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 m6A demethylases, has not been fully explored in HCC. Here we clarify the biological profile and potential mechanisms of ALKBH5 in HCC.MethodsExpression 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 m6A dot blot, MeRIP-qPCR, RIP-qPCR or dual luciferase reporter assays were employed to screen and validate the candidate targets of ALKBH5.ResultsWe 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 m6A demethylation led to a post-transcriptional inhibition of LY6/PLAUR Domain Containing 1 (LYPD1), which could be recognized and stabilized by the m6A 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.ConclusionOur study reveals that ALKBH5, characterized as a tumor suppressor, attenuates the expression of LYPD1 via an m6A-dependent manner in HCC cells. Our findings enrich the landscape of m6A-modulated tumor malignancy, and provide new insights into potential biomarkers and therapeutic targets of HCC treatment. More... »

PAGES

123

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s12943-020-01239-w

    DOI

    http://dx.doi.org/10.1186/s12943-020-01239-w

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1130007412

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/32772918


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