Novel Prognostic Implications of Methylated RNA and Demethylases in Resected HCC and Background Liver Tissue

Nakagawa, Nobuhiko; Tanaka, Kichinosuke; Sonohara, Fuminori; Kandimalla, Raju; Sunagawa, Yuki; Inokawa, Yoshikuni; Takami, Hideki; Hayashi, Masamichi; Yamada, Suguru; Kanda, Mitsuro; Tanaka, Chie; Nakayama, Goro; Koike, Masahiko; Kodera, Yasuhiro

doi:10.21873/anticanres.14690

Cited by 6 publications

(4 citation statements)

References 36 publications

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“…Several studies reported the increased ALKBH5 in HCC based on TCGA dataset [ 20 , 21 ] while other reports indicated decreased ALKBH5 in HCC [ 22 , 23 ], suggesting ALKBH5 might function differently in different HCC background (such as HBV versus non-HBV related HCC). To define ALKBH5 expression pattern in HBV-HCC, we collected 20 pairs of tumor and peri-tumor tissues with HBV infection history from Chinese patients.…”

Section: Resultsmentioning

confidence: 99%

A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis

Jin

Huang

et al. 2021

BMC Cancer

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Background Hepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people. Methods The expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells. Result ALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells’ growth and migration in vitro and in vivo. Conclusions HBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.

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Section: Resultsmentioning

confidence: 99%

A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis

Jin

Huang

et al. 2021

BMC Cancer

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“…FTO mRNA levels were reported to be significantly lower in HCC tissues. The expression of FTO was reduced in the HCC cells and was closely associated with AFP levels, tumor size, metastasis and vascular invasion 30 , 31 . Another study demonstrated that overexpression of FTO was associated with poor prognosis in HCC patients.…”

Section: The Roles Of M6a Modification In Hccmentioning

confidence: 99%

“…ALKBH5 expression in HCC tissues was significantly lower than that in normal tissues, and the absence of ALKBH5 predicted poor overall survival and disease-free survival in HCC patients [30,35]. ALKBH5-mediated m6A demethylation resulted in the posttranscriptional repression of LY6/PLAUR domain 1 (LYPD1), which could be stabilized by the m6A "reader" IGF2BP1.…”

Section: Alkbh5 and Hccmentioning

confidence: 99%

The functional roles, cross-talk and clinical implications of m6A modification and circRNA in hepatocellular carcinoma

Qin¹,

Mao²,

Xue³

et al. 2021

Int. J. Biol. Sci.

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. HCC has high rates of death and recurrence, as well as very low survival rates. N6-methyladenosine (m6A) is the most abundant modification in eukaryotic RNAs, and circRNAs are a class of circular noncoding RNAs that are generated by back-splicing and they modulate multiple functions in a variety of cellular processes. Although the carcinogenesis of HCC is complex, emerging evidence has indicated that m6A modification and circRNA play vital roles in HCC development and progression. However, the underlying mechanisms governing HCC, their cross-talk, and clinical implications have not been fully elucidated. Therefore, in this paper, we elucidated the biological functions and molecular mechanisms of m6A modification in the carcinogenesis of HCC by illustrating three different regulatory factors ("writer", "eraser", and "reader") of the m6A modification process. Additionally, we dissected the functional roles of circRNAs in various malignant behaviors of HCC, thereby contributing to HCC initiation, progression and relapse. Furthermore, we demonstrated the cross-talk and interplay between m6A modification and circRNA by revealing the effects of the collaboration of circRNA and m6A modification on HCC progression. Finally, we proposed the clinical potential and implications of m6A modifiers and circRNAs as diagnostic biomarkers and therapeutic targets for HCC diagnosis, treatment and prognosis evaluation.

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“…METTL3 is a biomarker of poor prognosis, and the abnormal upregulation of METTL3 expression in HCC results from CNV and DNA methylation rather than somatic mutation [ 116 ]. The low-expression of demethylases (mainly FTO and ALKBH5) and concomitant m6A modifications in noncancerous peritumoral liver tissues are believed to enhance the malignant potential of liver cancer after resection [ 117 ]. Overall, the main m6A regulatory factors related to HCC are YTHDF2, YTHDF1, METTL3, KIAA1429 and ZC3H13.…”

Section: Introductionmentioning

confidence: 99%

Function and clinical significance of N6-methyladenosine in digestive system tumours

Huang

Shao

2021

Exp Hematol Oncol

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RNA modification, like DNA methylation, histone modification, non-coding RNA modification and chromatin rearrangement, plays an important role in tumours. N6-methyladenosine (m6A) is the most abundant RNA modification in cells, and it regulates RNA transcription, processing, splicing, degradation, and translation. m6A-associated proteins have been used as new biomarkers and therapeutic targets for tumour prediction and monitoring. There are three main types of proteins involved in m6A methylation: methyltransferases (METTL3, METTL14, WTAP, RBM15, ZC3H13 and KIAA1429), demethylases (FTO, ALKBH5 and ALKBH3) and RNA-binding proteins (YTHDF1-3, YTHDC1-2, IGF2BPs and HNRNPs). This article reviews the origins, characteristics and functions of m6A and its relationship with digestive system tumours based on recent research. The expression of m6A regulators can be used as an evaluation indicator of tumour growth and progression and as a prognostic indicator. In-depth research on m6A methylation in digestive system tumours may provide new directions for clinical prediction and further treatment.

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Novel Prognostic Implications of Methylated RNA and Demethylases in Resected HCC and Background Liver Tissue

Cited by 6 publications

References 36 publications

A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis

A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis

The functional roles, cross-talk and clinical implications of m6A modification and circRNA in hepatocellular carcinoma

Function and clinical significance of N6-methyladenosine in digestive system tumours

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