Existing studies have underscored the pivotal role of N-acetyltransferase 10(NAT10) in various cancers. However, the outcomes of protein-protein interactions between NAT10 and its protein partners in head and neck squ...Existing studies have underscored the pivotal role of N-acetyltransferase 10(NAT10) in various cancers. However, the outcomes of protein-protein interactions between NAT10 and its protein partners in head and neck squamous cell carcinoma(HNSCC) remain unexplored. In this study, we identified a significant upregulation of RNA-binding protein with serine-rich domain 1(RNPS1) in HNSCC, where RNPS1 inhibits the ubiquitination degradation of NAT10 by E3 ubiquitin ligase, zinc finger SWIM domain-containing protein 6(ZSWIM6), through direct protein interaction, thereby promoting high NAT10 expression in HNSCC. This upregulated NAT10 stability mediates the enhancement of specific tRNA ac^(4)C modifications, subsequently boosting the translation process of genes involved in pathways such as IL-6 signaling, IL-8 signaling, and PTEN signaling that play roles in regulating HNSCC malignant progression, ultimately influencing the survival and prognosis of HNSCC patients. Additionally, we pioneered the development of TRMC-seq, leading to the discovery of novel t RNA-ac^(4)C modification sites, thereby providing a potent sequencing tool for tRNAac^(4)C research. Our findings expand the repertoire of tRNA ac^(4)C modifications and identify a role of tRNA ac^(4)C in the regulation of mRNA translation in HNSCC.展开更多
Objective:Anoikis is apoptosis that is induced when cells detach from the extracellular matrix and neighboring cells.As anoikis serves as a regulatory barrier,cancer cells often acquire resistance towards anoikis duri...Objective:Anoikis is apoptosis that is induced when cells detach from the extracellular matrix and neighboring cells.As anoikis serves as a regulatory barrier,cancer cells often acquire resistance towards anoikis during tumorigenesis to become metastatic.MicroRNAs(miRNAs)are short strand RNA molecules that regulate genes post-transcriptionally by binding to mRNAs and reducing the expression of its target genes.This study aimed to elucidate the role of a novel miRNA,miR-6744-5 p,in regulating anoikis in breast cancer and identify its target gene.Methods:An anoikis resistant variant of the luminal A type breast cancer MCF-7 cell line(MCF-7-AR)was generated by selecting and amplifying surviving cells after repeated exposure to growth in suspension.Mi RNA microarray analysis identified a list of dysregulated miRNAs from which miR-6744-5 p was chosen for overexpression and knockdown studies in MCF-7.Additionally,the miRNA was also overexpressed in a triple-negative breast cancer cell line,MDA-MB-231,to evaluate its ability to impair the metastatic potential of breast cancer cells.Results:This study showed that overexpression and knockdown of miR-6744-5 p in MCF-7 increased and decreased anoikis sensitivity,respectively.Similarly,overexpression of miR-6744-5 p in MDA-MB-231 increased anoikis and also decreased tumor cell invasion in vitro and in vivo.Furthermore,NAT1 enzyme was identified and validated as the direct target of miR-6744-5 p.Conclusions:This study has proven the ability of miR-6744-5 p to increase anoikis sensitivity in both luminal A and triple negative breast cancer cell lines,highlighting its therapeutic potential in treating breast cancer.展开更多
基金supported by the National Natural Science Foundation of China(82173362 and 81872409)the Guangdong Basic and Applied Basic Research Foundation(2019A1515110110)。
文摘Existing studies have underscored the pivotal role of N-acetyltransferase 10(NAT10) in various cancers. However, the outcomes of protein-protein interactions between NAT10 and its protein partners in head and neck squamous cell carcinoma(HNSCC) remain unexplored. In this study, we identified a significant upregulation of RNA-binding protein with serine-rich domain 1(RNPS1) in HNSCC, where RNPS1 inhibits the ubiquitination degradation of NAT10 by E3 ubiquitin ligase, zinc finger SWIM domain-containing protein 6(ZSWIM6), through direct protein interaction, thereby promoting high NAT10 expression in HNSCC. This upregulated NAT10 stability mediates the enhancement of specific tRNA ac^(4)C modifications, subsequently boosting the translation process of genes involved in pathways such as IL-6 signaling, IL-8 signaling, and PTEN signaling that play roles in regulating HNSCC malignant progression, ultimately influencing the survival and prognosis of HNSCC patients. Additionally, we pioneered the development of TRMC-seq, leading to the discovery of novel t RNA-ac^(4)C modification sites, thereby providing a potent sequencing tool for tRNAac^(4)C research. Our findings expand the repertoire of tRNA ac^(4)C modifications and identify a role of tRNA ac^(4)C in the regulation of mRNA translation in HNSCC.
基金funded by the University of Malaya Postgraduate Research grant(Grant No.PG021-2016A)the Research University CEBAR grant(Grant No.RU0152016)。
文摘Objective:Anoikis is apoptosis that is induced when cells detach from the extracellular matrix and neighboring cells.As anoikis serves as a regulatory barrier,cancer cells often acquire resistance towards anoikis during tumorigenesis to become metastatic.MicroRNAs(miRNAs)are short strand RNA molecules that regulate genes post-transcriptionally by binding to mRNAs and reducing the expression of its target genes.This study aimed to elucidate the role of a novel miRNA,miR-6744-5 p,in regulating anoikis in breast cancer and identify its target gene.Methods:An anoikis resistant variant of the luminal A type breast cancer MCF-7 cell line(MCF-7-AR)was generated by selecting and amplifying surviving cells after repeated exposure to growth in suspension.Mi RNA microarray analysis identified a list of dysregulated miRNAs from which miR-6744-5 p was chosen for overexpression and knockdown studies in MCF-7.Additionally,the miRNA was also overexpressed in a triple-negative breast cancer cell line,MDA-MB-231,to evaluate its ability to impair the metastatic potential of breast cancer cells.Results:This study showed that overexpression and knockdown of miR-6744-5 p in MCF-7 increased and decreased anoikis sensitivity,respectively.Similarly,overexpression of miR-6744-5 p in MDA-MB-231 increased anoikis and also decreased tumor cell invasion in vitro and in vivo.Furthermore,NAT1 enzyme was identified and validated as the direct target of miR-6744-5 p.Conclusions:This study has proven the ability of miR-6744-5 p to increase anoikis sensitivity in both luminal A and triple negative breast cancer cell lines,highlighting its therapeutic potential in treating breast cancer.
