Chronic myeloid leukemia(CML)is a common adult leukemia.Both the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor prognosis.The N6-methyladenine(m^(6)A)modification plays...Chronic myeloid leukemia(CML)is a common adult leukemia.Both the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor prognosis.The N6-methyladenine(m^(6)A)modification plays an important regulatory role in various physiological and pathological processes.KIAA1429 is a known m^(6)A regulator,but the biological role of KIAA1429 in CML is unclear.In this study,we observed that the m^(6)A levels and KIAA1429 expression were significantly up-regulated in patients with blast phase CML.Notably,KIAA1429 regulated the total level of RNA m^(6)A modification in the CML cells and promoted the malignant biological behaviors of CML cells,including proliferation,migration,and imatinib resistance.Inhibiting KIAA1429 in CML cells reduced the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis,consequently inhibiting CML proliferation and drug efflux,ultimately increasing the sensitivity of CML cells to imatinib.Moreover,the knockdown of RAB27B also inhibited the proliferation and drug resistance of CML cells and promoted their apoptosis.Rucaparib,a recently developed anti-cancer agent,suppressed the expression of KIAA1429 and CML cell proliferation and promoted cell apoptosis.Rucaparib also inhibited the tumorigenesis of CML cells in vivo.The combined use of rucaparib and imatinib enhanced the sensitivity of CML cells to imatinib.Our study provides evidence that elevated KIAA1429 expression in the blast phase of CML enhances the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis to up-regulate RAB27B expression,thereby promoting CML progression.Rucaparib exerts inhibitory effects on KIAA1429 expression and thus reduces CML progression.展开更多
Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reas...Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reasons for activation of KIAA1429(also known as VIRMA,an RNA methyltransferase)and its underlying mechanism in lung adenocarcinoma(LUAD)remain largely unexplored.In this study,we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD.Methods:Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase.The in vitro and in vivo functions of KIAA1429 were investigated.Transcriptome sequencing,methylated RNA immunoprecipitation sequencing(MeRIP-seq),m6A dot blot assays and RNA immunoprecipitation(RIP)were performed to confirm the modified gene mediated by KIAA1429.RNA stability assays were used to detect the half-life of the target gene.Results:Copy number amplification drove higher expression of KIAA1429 in LUAD,whichwas correlatedwith poor overall survival.Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD.Mechanistically,the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays.We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner.Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA,leading to enhanced YTH m6A RNA binding protein 2(YTHDF2,the m6A“reader”)-dependent BTG2 mRNA stability and promoted the expression of BTG2;thus,participating in the tumorigenesis of LUAD.Conclusions:Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis,which may provide a novel view on the targeted molecular therapy of LUAD.展开更多
Background:Lung adenocarcinoma(LUAD)is the most common lung cancer worldwide.N6-methyladenosine(m6A)methylation is a messenger RNA(mRNA)modification that plays a key role in tumor growth,immune microenvironment,and im...Background:Lung adenocarcinoma(LUAD)is the most common lung cancer worldwide.N6-methyladenosine(m6A)methylation is a messenger RNA(mRNA)modification that plays a key role in tumor growth,immune microenvironment,and immunotherapy response.This study investigated the expression level,mutation status,prognostic value,and predictive ability for response to anti-PD-1 immunotherapy of the m6A methyltransferase KIAA1429 in LUAD.Methods:This study examined multiple public data cohorts and independent samples from National Cancer Center(NCC)to evaluate the clinical significance and prognostic value of KIAA1429 in LUAD using bioinformatics techniques and immunohistochemical staining.We also evaluated the predictive value of KIAA1429 expression for anti-PD-1 immunotherapy efficacy.GSEA analysis was performed using KIAA1429 RNA-seq data at the tumor tissue level and cellular level to explore the potential molecular mechanism.Results:In public databases,KIAA1429 was significantly associated with clinicopathological parameters in LUAD patients and had the potential to predict patient prognosis.The mutation characteristics of KIAA1429-related genes were analyzed and TP53,TTN,CSMD3,and other genes showed high mutation frequencies in LUAD.An independent cohort of 415 samples confirmed that high KIAA1429 expression was significantly associated with poorer prognosis in LUAD patients.Analysis of a small immunotherapy cohort showed that patients with high expression of KIAA1429 had better response after immunotherapy,and the proportion of patients with immunotherapy response was higher in this group.Conclusions:Our study confirmed that KIAA1429 was highly expressed in LUAD and was significantly associated with poor prognosis.Moreover,KIAA1429 may serve as a potential marker to predict the efficacy of immunotherapy in LUAD.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.81860034,82160405,82160038,82260035)the Natural Science Foundations of Jiangxi Province,China(No.20224BAB216037,20212ACB 206016).
文摘Chronic myeloid leukemia(CML)is a common adult leukemia.Both the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor prognosis.The N6-methyladenine(m^(6)A)modification plays an important regulatory role in various physiological and pathological processes.KIAA1429 is a known m^(6)A regulator,but the biological role of KIAA1429 in CML is unclear.In this study,we observed that the m^(6)A levels and KIAA1429 expression were significantly up-regulated in patients with blast phase CML.Notably,KIAA1429 regulated the total level of RNA m^(6)A modification in the CML cells and promoted the malignant biological behaviors of CML cells,including proliferation,migration,and imatinib resistance.Inhibiting KIAA1429 in CML cells reduced the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis,consequently inhibiting CML proliferation and drug efflux,ultimately increasing the sensitivity of CML cells to imatinib.Moreover,the knockdown of RAB27B also inhibited the proliferation and drug resistance of CML cells and promoted their apoptosis.Rucaparib,a recently developed anti-cancer agent,suppressed the expression of KIAA1429 and CML cell proliferation and promoted cell apoptosis.Rucaparib also inhibited the tumorigenesis of CML cells in vivo.The combined use of rucaparib and imatinib enhanced the sensitivity of CML cells to imatinib.Our study provides evidence that elevated KIAA1429 expression in the blast phase of CML enhances the stability of RAB27B mRNA through the m^(6)A/YTHDF1 axis to up-regulate RAB27B expression,thereby promoting CML progression.Rucaparib exerts inhibitory effects on KIAA1429 expression and thus reduces CML progression.
基金Science Fund for Creative Research Groups of the National Natural Science Foundation of China,Grant/Award Number:81521004National Natural Science Foundation of China,Grant/Award Numbers:81922061,82172992,81903391,81702266+2 种基金Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancers,Chinese Academy of Medical Sciences,Grant/Award Number:2019RU038Natural Science Foundation of Jiangsu Province,Grant/Award Numbers:BK20211253,BK20190148Postgraduate Research&Practice Innovation Program of Jiangsu Province,Grant/Award Number:KYCX18_0195。
文摘Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reasons for activation of KIAA1429(also known as VIRMA,an RNA methyltransferase)and its underlying mechanism in lung adenocarcinoma(LUAD)remain largely unexplored.In this study,we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD.Methods:Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase.The in vitro and in vivo functions of KIAA1429 were investigated.Transcriptome sequencing,methylated RNA immunoprecipitation sequencing(MeRIP-seq),m6A dot blot assays and RNA immunoprecipitation(RIP)were performed to confirm the modified gene mediated by KIAA1429.RNA stability assays were used to detect the half-life of the target gene.Results:Copy number amplification drove higher expression of KIAA1429 in LUAD,whichwas correlatedwith poor overall survival.Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD.Mechanistically,the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays.We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner.Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA,leading to enhanced YTH m6A RNA binding protein 2(YTHDF2,the m6A“reader”)-dependent BTG2 mRNA stability and promoted the expression of BTG2;thus,participating in the tumorigenesis of LUAD.Conclusions:Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis,which may provide a novel view on the targeted molecular therapy of LUAD.
基金National Natural Science Foundation of China,Grant/Award Number:82002451Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2018PT32033+3 种基金Special Research Fund for Central Universities,Peking Union Medical College,Grant/Award Number:3332020024National Key R&D Program of China,Grant/Award Number:2021YFC2500900Beijing Hope Run Special Fund of Cancer Foundation of China,Grant/Award Number:LC2019B15CAMS Initiative for Innovative Medicine,Grant/Award Number:2021-1-I2M-015。
文摘Background:Lung adenocarcinoma(LUAD)is the most common lung cancer worldwide.N6-methyladenosine(m6A)methylation is a messenger RNA(mRNA)modification that plays a key role in tumor growth,immune microenvironment,and immunotherapy response.This study investigated the expression level,mutation status,prognostic value,and predictive ability for response to anti-PD-1 immunotherapy of the m6A methyltransferase KIAA1429 in LUAD.Methods:This study examined multiple public data cohorts and independent samples from National Cancer Center(NCC)to evaluate the clinical significance and prognostic value of KIAA1429 in LUAD using bioinformatics techniques and immunohistochemical staining.We also evaluated the predictive value of KIAA1429 expression for anti-PD-1 immunotherapy efficacy.GSEA analysis was performed using KIAA1429 RNA-seq data at the tumor tissue level and cellular level to explore the potential molecular mechanism.Results:In public databases,KIAA1429 was significantly associated with clinicopathological parameters in LUAD patients and had the potential to predict patient prognosis.The mutation characteristics of KIAA1429-related genes were analyzed and TP53,TTN,CSMD3,and other genes showed high mutation frequencies in LUAD.An independent cohort of 415 samples confirmed that high KIAA1429 expression was significantly associated with poorer prognosis in LUAD patients.Analysis of a small immunotherapy cohort showed that patients with high expression of KIAA1429 had better response after immunotherapy,and the proportion of patients with immunotherapy response was higher in this group.Conclusions:Our study confirmed that KIAA1429 was highly expressed in LUAD and was significantly associated with poor prognosis.Moreover,KIAA1429 may serve as a potential marker to predict the efficacy of immunotherapy in LUAD.
