METTL3-mediated m6A methylation of SPHK2 promotes gastric cancer progression by targeting KLF2

Huo, Fu‐Chun; Zhu, Zhansheng; Zhu, Wentao; Du, Qiu-Ying; Liang, Jia; Mou, Jie

doi:10.1038/s41388-021-01753-1

Cited by 64 publications

(41 citation statements)

References 43 publications

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“…METTL3 increases miR-1246 levels through m6A modification, thereby promoting non-small-cell lung cancer progression [ 37 ]. Moreover, METTL3 regulates the m6A modification of SPHK2 to promote the progression of gastric cancer [ 38 ]. These findings verified the role of METTL3 in cancers such as CRC.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Zinc finger MYM-type containing 1 (ZMYM1) was also recognized as an m6A target of METTL3 to facilitate metastasis by recruiting a complex to mediate the expression of E-cadherin [ 17 ]. SPHK2 and MYC are also regulated by METTL3 to potentiate migration and invasion [ 19 , 20 ]. As a dynamic regulated system, the whole level of m6A modification was co-regulated by its “writers” and “erasers”.…”

Section: Introductionmentioning

confidence: 99%

Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification

Gong

et al. 2022

Mol Cancer

128

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Background Gastric cancer (GC) is one of the most pernicious tumors that seriously harm human healthcare. GC metastasis is one of the prime cause of failed cancer treatment, but correlation between N6-methyladenosine (m6A) and GC metastasis was less reported. Methods Methylated RNA immunoprecipitation sequencing (MeRIP-seq) of GC tissues was conducted. Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) were taken to determine the expression of ALKBH5 in GC tissues and cell lines. RNA-seq together with MeRIP-qRT-PCR was used to screen the target gene of ALKBH5. RNA pulldown, mass spectrometry and RNA immunoprecipitation (RIP) were used to search the “reader” protein of target gene. The mechanism was also validated via a tail vein injection method for lung metastasis model. Results Decreased expression of ALKBH5 was detected in GC samples, and it was correlated with clinical tumor distal metastasis and lymph node metastasis. ALKBH5 interference promoted metastasis of GC cells and this effect was closely related to the demethylase activity of ALKBH5. PKMYT1, as a downstream target of ALKBH5, promoted invasion and migration in GC. Caused by ALKBH5 knockdown or its demethylase activity mutation, upregulated expression of PKMYT1 indicated that ALKBH5 modulates expression of PKMYT1 in an m6A-dependent manner. IGF2BP3 helped stabilize the mRNA stability of PKMYT1 via its m6A modification site. Conclusions This study established an ALKBH5-PKMYT1-IGF2BP3 regulation system in metastasis, representing a new therapeutic target for GC metastasis.

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“…In the past few decades, several pivotal regulators are reported to participate in GC's pathogenesis (8,9). For example, METTL3-mediated m 6 A methylation of SPHK2 targets KLF2, thus promoting advanced GC (10). Human CCR4 and CAF1 deacetylase mediate the regulation of human GC cell proliferation and tumorigenicity via modulating the cell cycle process (11).…”

Section: Introductionmentioning

confidence: 99%

Identification and Validation of the Immune Regulator CXCR4 as a Novel Promising Target for Gastric Cancer

Xue

Bei

et al. 2021

Front. Immunol.

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Immune checkpoint blockade has attracted a lot of attention in the treatment of human malignant tumors. We are trying to establish a prognostic model of gastric cancer (GC) based on the expression profile of immunoregulatory factor-related genes. Based on the TCGA database, we identified 234 differentially expressed immunoregulatory factors. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) conducted enrichment analysis to clarify the biological functions of differential expression of immunoregulatory factors. STRING database predicted the interaction network between 234 differently expressed immune regulatory factors. The expression of 11 immunoregulatory factors was significantly related to the overall survival of gastric cancer patients. Univariate Cox regression analysis, Kaplan–Meier analysis and multivariate Cox regression analysis found that immunomodulatory factors were involved in the progression of gastric cancer and promising biomarkers for predicting prognosis. Among them, CXCR4 was related to the low survival of GC patients and a key immunomodulatory factor in GC. Based on TCGA data, the high expression of CXCR4 in GC was positively correlated with the advanced stage and grade of gastric cancer and related to poor prognosis. Univariate analysis and multivariate analysis indicated that CXCR4 was an independent prognostic indicator for TCGA gastric cancer patients. In vitro functional studies had shown that CXCR4 promoted the proliferation, migration, and invasion of gastric cancer cells. In summary, this study has determined the prognostic value of 11 immunomodulatory factors in gastric cancer. CXCR4 is an independent prognostic indicator for gastric cancer patients, which may help to improve the individualized prognostic prediction of GC and provide candidates for the diagnosis and treatment of GC.

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METTL3-mediated m6A methylation of SPHK2 promotes gastric cancer progression by targeting KLF2

Cited by 64 publications

References 43 publications

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

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

Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification

Identification and Validation of the Immune Regulator CXCR4 as a Novel Promising Target for Gastric Cancer

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