AMD1 upregulates hepatocellular carcinoma cells stemness by FTO mediated mRNA demethylation

Bian, Xinyu; Shi, Dongmin; Xing, Kailin; Zhou, Hongxin; Lü, Lili; Yu, Dahai; Wu, Wei‐Zhong

doi:10.1002/ctm2.352

Cited by 54 publications

(42 citation statements)

References 67 publications

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“…Although it is reported that m6A modification is involved in different biological and pathological processes [ 18 ], the underlying mechanisms of m6A that participated in PCa progression remain largely unknown. Our results suggested an unusual tumor suppressor role in PCa, which is known as an oncogene in other types of tumors [ 19 – 21 ]. We demonstrated that FTO is downregulated in prostate adenocarcinoma, and the downregulation of FTO was negatively correlated with disease-free survival.…”

Section: Discussionmentioning

confidence: 62%

N6-methyladenosine demethylase FTO suppressed prostate cancer progression by maintaining CLIC4 mRNA stability

et al. 2022

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The fat mass and obesity-associated protein (FTO) is an N6-Methyladenosine (m6A) demethylase, which has been revealed to play critical roles in tumorigenesis. However, its role in the development and progression of prostate cancer (PCa) remains poorly understood. Here, we aimed to investigate the function and clinical relevance of FTO in PCa. Our results demonstrated that FTO was notably downregulated in PCa tissues compared with the paired normal tissues. In addition, the decreased expression of FTO was correlated with poor prognosis of PCa. Functional experiments showed that depletion of FTO promoted the proliferation and metastasis of PCa both in vitro and in vivo. Conversely, ectopic expression of FTO exhibited the opposite effects. Combined with RNA-sequencing, MeRIP-RT-qPCR, and mRNA stability assays indicated chloride intracellular channel 4(CLIC4) was a functional target of FTO-mediated m6A modification. FTO depletion significantly increased the m6A level of CLIC4 mRNA and then reduced the mRNA stability. In conclusion, our findings suggest that FTO suppresses PCa proliferation and metastasis through reducing the degradation of CLIC4 mRNA in an m6A dependent manner. FTO may be used as a promising novel therapeutic target and prognostic evaluation biomarker for PCa.

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Section: Discussionmentioning

confidence: 62%

N6-methyladenosine demethylase FTO suppressed prostate cancer progression by maintaining CLIC4 mRNA stability

et al. 2022

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“…METTL3 and METTL14 can regulate the progression of multiple types of cancer, including bladder cancer [ 15 , 16 ], gastric cancer [ 17 , 18 ], cervical cancer [ 19 ], hepatocellular carcinoma [ 14 , 20 ], and pancreatic cancer [ 21 ]. FTO plays a central role in oral squamous cell carcinoma [ 22 ], hepatocellular carcinoma [ 23 ], bladder cancer [ 24 ], and acute myeloid leukemia [ 9 , 25 ]. Although studies have also demonstrated that m6A modification plays a key role in CRC [ 4 , 12 ], the function and regulatory mechanism of m6A in CRC progression remain unclear.…”

Section: Introductionmentioning

confidence: 99%

METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

Pan

Liu

Xiao

et al. 2022

J Exp Clin Cancer Res

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Background Colorectal carcinoma (CRC) is the third most common cancer and second most common cause of cancer-related deaths worldwide. Ribonucleic acid (RNA) N6-methyladnosine (m6A) and methyltransferase-like 3 (METTL3) play key roles in cancer progression. However, the roles of m6A and METTL3 in CRC progression require further clarification. Methods Adenoma and CRC samples were examined to detect m6A and METTL3 levels, and tissue microarrays were performed to evaluate the association of m6A and METTL3 levels with the survival of patients with CRC. The biological functions of METTL3 were investigated through cell counting kit-8, wound healing, and transwell assays. M6A epitranscriptomic microarray, methylated RNA immunoprecipitation-qPCR, RNA stability, luciferase reporter, and RNA immunoprecipitation assays were performed to explore the mechanism of METTL3 in CRC progression. Results M6A and METTL3 levels were substantially elevated in CRC tissues, and patients with CRC with a high m6A or METTL3 levels exhibited shorter overall survival. METTL3 knockdown substantially inhibited the proliferation, migration, and invasion of CRC cells. An m6A epitranscriptomic microarray revealed that the cell polarity regulator Crumbs3 (CRB3) was the downstream target of METTL3. METTL3 knockdown substantially reduced the m6A level of CRB3, and inhibited the degradation of CRB3 mRNA to increase CRB3 expression. Luciferase reporter assays also showed that the transcriptional level of wild-type CRB3 significantly increased after METTL3 knockdown but not its level of variation. Knockdown of YT521-B homology domain–containing family protein 2 (YTHDF2) substantially increased CRB3 expression. RNA immunoprecipitation assays also verified the direct interaction between the YTHDF2 and CRB3 mRNA, and this direct interaction was impaired after METTL3 inhibition. In addition, CRB3 knockdown significantly promoted the proliferation, migration, and invasion of CRC cells. Mechanistically, METTL3 knockdown activated the Hippo pathway and reduced nuclear localization of Yes1-associated transcriptional regulator, and the effects were reversed by CRB3 knockdown. Conclusions M6A and METTL3 levels were substantially elevated in CRC tissues relative to normal tissues. Patients with CRC with high m6A or METTL3 levels exhibited shorter overall survival, and METTL3 promoted CRC progression. Mechanistically, METTL3 regulated the progression of CRC by regulating the m6A–CRB3–Hippo pathway.

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“…YTHDF1 expression, mediated by HIF-1α, supports that hypoxic stress might lead to the alteration of cancer epigenetics, such as the translation of m6A-modified oncogenic mRNAs, to facilitate HCC malignancy. A recent study corroborated that AMD1 expression is the independent factor for overall survival (OS) and disease-free survival (DFS) in HCC ( Bian et al, 2021 ). Several investigations found high expression of AMD1 in HCC tissue and showed that AMD1 regulates the expression of NANOG, SOX2, and KLF4, which are involved in HCC initiation, metastasis, and chemoresistance.…”

Section: Mechanism Of Rna Methylation In Hccmentioning

confidence: 81%

Role of Main RNA Methylation in Hepatocellular Carcinoma: N6-Methyladenosine, 5-Methylcytosine, and N1-Methyladenosine

Zhang

et al. 2021

Front. Cell Dev. Biol.

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RNA methylation is considered a significant epigenetic modification, a process that does not alter gene sequence but may play a necessary role in multiple biological processes, such as gene expression, genome editing, and cellular differentiation. With advances in RNA detection, various forms of RNA methylation can be found, including N6-methyladenosine (m6A), N1-methyladenosine (m1A), and 5-methylcytosine (m5C). Emerging reports confirm that dysregulation of RNA methylation gives rise to a variety of human diseases, particularly hepatocellular carcinoma. We will summarize essential regulators of RNA methylation and biological functions of these modifications in coding and noncoding RNAs. In conclusion, we highlight complex molecular mechanisms of m6A, m5C, and m1A associated with hepatocellular carcinoma and hope this review might provide therapeutic potent of RNA methylation to clinical research.

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AMD1 upregulates hepatocellular carcinoma cells stemness by FTO mediated mRNA demethylation

Abstract: AMD1 could stabilize the interaction of IQGAP1 with FTO. The interaction with IQGAP1 increases FTO phosphorylation and expression. High level of FTO promotes pluripotency factors expression and elevates stem cell-like property of HCC cells.

Cited by 54 publications

References 67 publications

N6-methyladenosine demethylase FTO suppressed prostate cancer progression by maintaining CLIC4 mRNA stability

N6-methyladenosine demethylase FTO suppressed prostate cancer progression by maintaining CLIC4 mRNA stability

METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

Role of Main RNA Methylation in Hepatocellular Carcinoma: N6-Methyladenosine, 5-Methylcytosine, and N1-Methyladenosine

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