LINC00662 promotes hepatocellular carcinoma progression via altering genomic methylation profiles

Abstract

The identification of viability-associated long noncoding RNAs (lncRNAs) is a means of uncovering therapeutic approaches for hepatocellular carcinoma (HCC). In addition, aberrant genome-wide hypomethylation has been implicated in HCC initiation and progression. However, the relationship between lncRNA dysregulation and genome-wide hypomethylation in hepatocarcinogenesis has not been fully elucidated. A novel lncRNA named LINC00662 was previously demonstrated to play a role in gastrointestinal cancer. In this study, we demonstrated that this lncRNA was correlated with survival and exhibited oncogenic properties, both in vitro and in vivo. Moreover, we determined that LINC00662 could lead to genome-wide hypomethylation and alter the genomic methylation profile by synchronously reducing the S-adenosylmethionine (SAM) level and enhancing the S-adenosylhomocysteine (SAH) level. Mechanistically, LINC00662 was determined to regulate the key enzymes influencing SAM and SAH levels, namely, methionine adenosyltransferase 1A (MAT1A) and S-adenosylhomocysteine hydrolase (AHCY), by RNA–RNA and RNA–protein interactions. In addition, we demonstrated that some SAM-dependent HCC-promoting genes could be regulated by LINC00662 by altering the methylation status of their promoters via the LINC00662-coupled axes of MAT1A/SAM and AHCY/SAH. Taken together, the results of this this study indicate that LINC00662 could be a potential biomarker for HCC therapy. More importantly, we proposed a new role of lncRNA in regulating genomic methylation to promote oncogene activation.

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Fig. 1: LINC00662 was upregulated in HCC tissues and correlated with survival.
Fig. 2: LINC00662 promotes oncogenic behaviors in vitro.
Fig. 3: LINC00662 promotes oncological behaviors in vivo.
Fig. 4: LINC00662 is negatively correlated with genomic methylation and associates with aberrant SAM and SAH levels.
Fig. 5: LINC00662 leads to genomic hypomethylation and alters the genomic methylation profile patterns.
Fig. 6: LINC00662 was negatively correlated with MAT1A and AHCY.
Fig. 7: LINC00662 downregulates MAT1A mRNA by binding its 3′UTR.
Fig. 8: LINC00662 suppresses AHCY protein by inducing its ubiquitin-mediated degradation.
Fig. 9: LINC00662 maintains genomic hypomethylation to promote oncogene activation.

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Funding

This work was supported by the Fundamental Research Funds for the Central Universities (No. 2042018kf0079); Hubei Province Natural Science Foundation of China (No. 2018CFB157); National Natural Science Foundation of China (No. 81800522).

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Correspondence to Zhen Li.

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The related protocols were approved by the Human Subjects Committee of Zhongnan Hospital according to the Declaration of Helsinki. Written informed consent was obtained from all patients.

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Guo, T., Gong, C., Wu, P. et al. LINC00662 promotes hepatocellular carcinoma progression via altering genomic methylation profiles. Cell Death Differ (2020). https://doi.org/10.1038/s41418-020-0494-3

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