Dysregulated m6A modification promotes lipogenesis and development of non-alcoholic fatty liver disease and hepatocellular carcinoma

Yang, Yeming; Cai, Jingshu; Yang, Xue; Wang, Kaifang; Sun, Kuanxiang; Yang, Zhenglin; Zhang, Lin; Lü, Yang; Gu, Chun Ping; Huang, Xiang; Wang, Ziyan; Zhu, Xuejun

doi:10.1016/j.ymthe.2022.02.021

Cited by 75 publications

(49 citation statements)

References 41 publications

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“…Fatty acid synthase (FASN), acetyl-CoA carboxylase (ACCY), and stearoyl-CoA desaturase 1 (SCD1) are the regulator targets, as recently reported ( Figure 1 ). Mechanistically, METTL3/METTL14 complex induces the increase of mRNA to accelerate the production of lipid ( 48 , 49 ). Consistently, METTL3 and the recognizing and binding protein YTHDF2 increase the m6A methylation level of peroxisome proliferator-activated receptorα(PPARα) and its expression, impacting the downstream lipid accumulation ( 50 ).…”

Section: Rna M6a Methylation Regulates the Lipid Metabolismmentioning

confidence: 99%

The role of RNA m6A methylation in lipid metabolism

Wang

et al. 2022

Front. Endocrinol.

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The m6A methylation is the most numerous modification of mRNA in mammals, coordinated by RNA m6A methyltransferases, RNA m6A demethylases, and RNA m6A binding proteins. They change the RNA m6A methylation level in their specific manner. RNA m6A modification has a significant impact on lipid metabolic regulation. The “writer” METTL3/METTL14 and the “eraser” FTO can promote the accumulation of lipids in various cells by affecting the decomposition and synthesis of lipids. The “reader” YTHDF recognizes m6A methylation sites of RNA and regulates the target genes’ translation. Due to this function that regulates lipid metabolism, RNA m6A methylation plays a pivotal role in metabolic diseases and makes it a great potential target for therapy.

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Section: Rna M6a Methylation Regulates the Lipid Metabolismmentioning

confidence: 99%

The role of RNA m6A methylation in lipid metabolism

Wang

et al. 2022

Front. Endocrinol.

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“…Promotes FA synthesis and lipid accumulation [114] CRC Tumor suppressor miR-375 YAP1/SP1 Suppresses migration, invasion, proliferation [94] Tumor suppressor KLF4 IGF2BP2 Suppresses migration and invasion [115] Tumor suppressor ARRDC4 HuR TCF4…”

Section: Liver Cancermentioning

confidence: 99%

“…However, Yang et al proposed the opposite role of METTL14 in HCC, they detected upregulated level of METTL14 in both HCC cells and patient samples. It was demonstrated that overexpressed METTL14 stabilized m6A-modified ATP citrate lyase (ACLY) and stearoyl-CoA desaturase 1 (SCD1) mRNA to increase their expression, thereafter aggravated FA synthesis and lipid accumulation, which contributed to DNA damage, chronic inflammation, cell apoptosis, excessive compensatory cell proliferation in livers, further developing non-alcohol Fatty Liver Disease (NAFLD) and HCC [ 114 ]. In conclusion, these findings suggested the important impact of METTL14 on LC.…”

Section: Introductionmentioning

confidence: 99%

The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer

et al. 2022

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Gastrointestinal cancer is the most common human malignancy characterized by high lethality and poor prognosis. Emerging evidences indicate that N6-methyladenosine (m6A), the most abundant post-transcriptional modification in eukaryotes, exerts important roles in regulating mRNA metabolism including stability, decay, splicing, transport, and translation. As the key component of the m6A methyltransferase complex, methyltransferase-like 14 (METTL14) catalyzes m6A methylation on mRNA or non-coding RNA to regulate gene expression and cell phenotypes. Dysregulation of METTL14 was deemed to be involved in various aspects of gastrointestinal cancer, such as tumorigenesis, progression, chemoresistance, and metastasis. Plenty of findings have opened up new avenues for exploring the therapeutic potential of gastrointestinal cancer targeting METTL14. In this review, we systematically summarize the recent advances regarding the biological functions of METTL14 in gastrointestinal cancer, discuss its potential clinical applications and propose the research forecast.

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“…m 6 A modification mediated by ALKBH5 upregulated LINC01468 Since m 6 A dysregulation enhances lipogenesis and NAFLD-HCC progression [42], we analyzed whether LINC01468 was modified or upregulated by m 6 A modification. Many m 6 A sites were found with LINC01468 using the RMvar (rmvar.renlab.org) prediction.…”

Section: Linc01468 Destabilizes Ship2 Via Ubiquitin Proteasome Pathwaymentioning

confidence: 99%

LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2

Wang

Lai

et al. 2022

Cell Death Discov.

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Accumulating evidence suggests that long noncoding RNAs (lncRNAs) are deregulated in hepatocellular carcinoma (HCC) and play a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the current understanding of the role of lncRNAs in NAFLD-associated HCC is limited. In this study, transcriptomic profiling analysis of three paired human liver samples from patients with NAFLD-driven HCC and adjacent samples showed that LINC01468 expression was significantly upregulated. In vitro and in vivo gain- and loss-of-function experiments showed that LINC01468 promotes the proliferation of HCC cells through lipogenesis. Mechanistically, LINC01468 binds SHIP2 and promotes cullin 4 A (CUL4A)-linked ubiquitin degradation, thereby activating the PI3K/AKT/mTOR signaling pathway, resulting in the promotion of de novo lipid biosynthesis and HCC progression. Importantly, the SHIP2 inhibitor reversed the sorafenib resistance induced by LINC01468 overexpression. Moreover, ALKBH5-mediated N6-methyladenosine (m6A) modification led to stabilization and upregulation of LINC01468 RNA. Taken together, the findings indicated a novel mechanism by which LINC01468-mediated lipogenesis promotes HCC progression through CUL4A-linked degradation of SHIP2. LINC01468 acts as a driver of HCC progression from NAFLD, highlights the potential of the LINC01468-SHIP2 axis as a therapeutic target for HCC.

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Dysregulated m6A modification promotes lipogenesis and development of non-alcoholic fatty liver disease and hepatocellular carcinoma

Cited by 75 publications

References 41 publications

The role of RNA m6A methylation in lipid metabolism

The role of RNA m6A methylation in lipid metabolism

The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer

LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2

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