Comprehensive analysis of 5‐hydroxymethylcytosine in zw10 kinetochore protein as a promising biomarker for screening and diagnosis of early colorectal cancer

Dang, Yanqi; Hu, Dan; Xu, Jing-Juan; Li, Chunlin; Tang, Yiming; Yang, Zhenhua; Liu, Yang; Zhou, Wenjun; Zhang, Li; Xu, Hanchen; Xu, Yangxian; Ji, Guang

doi:10.1002/ctm2.125

Cited by 12 publications

(16 citation statements)

References 48 publications

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“…The 5-year survival rate of patients with CRC is 65% [ 32 ], but it is extremely low in advanced-stage CRC. Therefore, techniques that aid the implementation of treatment strategies for CRC are urgently required because they can improve patient survival [ 27 ]. Studies have reported that m6A modification plays a key role in CRC [ 4 , 5 , 12 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, 293 T cells obtained from the American Type Culture Collection were cultured in Roswell Park Memorial Institute 1640 Medium with 10% FBS and penicillin/streptomycin (100 U/mL; Gibco, USA). METTL3 short hairpin RNA plasmid, CRB3 short hairpin RNA plasmid, or negative control (Genomeditech, China) were transfected using FuGene HD transfection reagent (E2311, Promega, USA) per the protocol used in a previous study [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

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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%

Section: Methodsmentioning

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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“…Colon cancer is a very common cancer worldwide with high morbidity and mortality. Several kinetochore proteins have been identified as a novel regulator of carcinogenesis in colorectal cancer (Dang et al 2020;Bai et al Zhou et al 2020;Zhang et al 2021). In the present study, KNTC1, a key kinetochore component, was shown to be overexpressed in colon cancer tissues.…”

Section: Discussionmentioning

confidence: 99%

KNTC1 knockdown suppresses cell proliferation of colon cancer

et al. 2021

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Kinetochore-associated protein 1 (KNTC1) is a kind of kinetochore components that ensure the proper functioning of the spindle-assembly checkpoint. To date, the functional information of KNTC1 in colon cancer remains unknown. This study was aimed to investigate the role of KNTC1 in colon cancer. We found KNTC1 was significantly upregulated in the colon cancer compared to the normal tissues. ROC curve showed the area under the curve value of KNTC1 for the prediction of colon cancer was 0.93. Kaplan-Meier revealed highly expressed KNTC1 was associated with poor prognosis. KNTC1 was widely expressed in different colon cancer cell lines. Compared with the control lentiviral infected cells, KNTC1-shRNA cells exhibited significant reduction in cell growth rates and increase in the proportion of cells in the S phase, while decrease in the G1 and G2/M phase. Furthermore, knockdown of KNTC1 dramatically increased apoptosis in the colon cancer cells. Gene set enrichment analysis (GSEA) in gene ontology (GO) showed that KNTC1 is closely associated with cell mitosis-related components, such as nuclear chromatin, centrosome, and spindle. Moreover, upregulated KNTC1 is significantly enriched in the biological process of DNA repair, mRNA processing, microtubule cytoskeleton organization and the molecular function of helicase activity, protein heterodimerization activity and catalytic activity acting on DNA in molecular function. Our data reveal the important roles of KNTC1 in driving tumor progression in colon cancers. KeywordsKNTC1 • Colon cancer • Cell growth • GSEA * Yang Zhimin

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“…Although the ve-year survival rate of CRC patients is 65% [32], the ve-year survival rate of patients with advanced-stage CRC is very low. Therefore, it is urgent to develop techniques for the treatment strategy of CRC, which would improve patient survival [27]. Studies have indicated that m6A modi cation plays a critical role in CRC [4,5,12,33].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, 293T cells obtained from ATCC were cultured in RPMI Medium 1640 with 10% fetal bovine serum and penicillin/streptomycin (100 U/mL) (Gibco, Carlsbad, USA). METTL3 short hairpin RNA plasmid (sh-METTL3), CRB3 short hairpin RNA plasmid (sh-CRB3) or negative control (sh-NC) (Genomeditech, China) were transfected using FuGene® HD transfection reagent (Promega, USA) according to a previous study [27].…”

Section: Cell Culture and Transfectionmentioning

confidence: 99%

METTL3 Facilitates Colorectal Carcinoma Progression via Regulating m6A-CRB3-Hippo Axis

Liu¹,

Xiao²,

Pan³

et al. 2021

Preprint

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Background Colorectal carcinoma (CRC) is the third most common cancer and the second most common cause of cancer-related death worldwide. RNA N6-methyladnosine (m6A) and methyltransferase-like 3 (METTL3) play an important role in cancer. However, the roles of m6A and METTL3 in CRC progression are still elusive. Methods Adenoma and CRC samples were applied to detect m6A and METTL3 levels, and tissue microarrays were performed to evaluate their associations with survival of CRC patients. The biological functions of METTL3 were investigated by CCK8, wound healing and transwell assays. M6A epitranscriptomic microarray, RNA stability and luciferase reporter assays were performed to explore the mechanism of METTL3 in CRC. Results m6A and METTL3 levels were significantly upregulated in both adenoma and CRC tissues, and the CRC patients with high m6A or METTL3 level had both shorter overall survival. METTL3 knockdown markedly inhibited the proliferation, migration and invasion of CRC cells. M6A epitranscriptomic microarray revealed that the cell polarity regulator Crumbs3 (CRB3) was the downstream target of METTL3. METTL3 knockdown markedly inhibited the degradation of CRB3 mRNA to increase the CRB3 expression. In addition, CRB3 level was also markedly reduced in both adenoma and CRC tissues, and the CRC patients with high CRB3 level had higher overall survival and disease free survival. CRB3 knockdown significantly promoted the proliferation, migration and invasion of CRC cells. Finally, CRB3 knockdown inhibited Hippo pathway, and increased nuclear localization of YAP. Conclusions The m6A and METTL3 levels were significantly increased in both adenoma and CRC tissues. The CRC patients with high m6A or METTL3 levels had shorter overall survival. Mechanistically, METTL3 regulated the initiation and progression of CRC via regulating m6A-CRB3-Hippo pathway.

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Comprehensive analysis of 5‐hydroxymethylcytosine in zw10 kinetochore protein as a promising biomarker for screening and diagnosis of early colorectal cancer

Cited by 12 publications

References 48 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

KNTC1 knockdown suppresses cell proliferation of colon cancer

METTL3 Facilitates Colorectal Carcinoma Progression via Regulating m6A-CRB3-Hippo Axis

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