RNA bisulfite sequencing reveals NSUN2-mediated suppression of epithelial differentiation in pancreatic cancer
Posttranscriptional modifications in RNA have been considered to contribute to disease pathogenesis and tumor progression. NOL1/NOP2/Sun domain family member 2 (NSUN2) is an RNA methyltransferase that promotes tumor progression in several cancers. Pancreatic cancer relapse inevitably occurs even in...
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| Veröffentlicht in: | Oncogene 2022-05, Vol.41 (22), p.3162-3176 |
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| creator | Chen, Szu-Ying Chen, Kuan-Lin Ding, Li-Yun Yu, Chien-Hung Wu, Hsin-Yi Chou, Ya-Yi Chang, Chia-Jung Chang, Chih-Han Wu, Ya-Na Wu, Shang-Rung Hou, Ya-Chin Lee, Chung-Ta Chen, Peng-Chieh Shan, Yan-Shen Huang, Po-Hsien |
| description | Posttranscriptional modifications in RNA have been considered to contribute to disease pathogenesis and tumor progression. NOL1/NOP2/Sun domain family member 2 (NSUN2) is an RNA methyltransferase that promotes tumor progression in several cancers. Pancreatic cancer relapse inevitably occurs even in cases where primary tumors have been successfully treated. Associations of cancer progression due to reprogramming of the cancer methyl-metabolome and the cancer genome have been noted, but the effect of base modifications, namely 5-methylcytosine (m
5
C), in the transcriptome remains unclear. Aberrant regulation of 5-methylcytosine turnover in cancer may affect posttranscriptional modifications in coding and noncoding RNAs in disease pathogenesis. Mutations in NSUN2 have been reported as drivers of neurodevelopmental disorders in mice, and upregulated expression of NSUN2 in tumors of the breast, bladder, and pancreas has been reported. In this study, we conducted mRNA whole transcriptomic bisulfite sequencing to categorize NSUN2 target sites in the mRNA of human pancreatic cancer cells. We identified a total of 2829 frequent m
5
C sites in mRNA from pancreatic cancer cells. A total of 90.9% (2572/2829) of these m
5
C sites were mapped to annotated genes in autosomes and sex chromosomes X and Y. Immunohistochemistry staining confirmed that the NSUN2 expression was significantly upregulated in cancer lesions in the
LSL-Kras
G12D/+
;Trp53
fl/fl
;Pdx1-Cre
(KPC) spontaneous pancreatic cancer mouse model induced by Pdx1-driven Cre/lox system expressing mutant Kras
G12D
and p53 deletion. The in vitro phenotypic analysis of NSUN2 knockdown showed mild effects on pancreatic cancer cell 2D/3D growth, morphology and gemcitabine sensitivity in the early phase of tumorigenesis, but cumulative changes after multiple cell doubling passages over time were required for these mutations to accumulate. Syngeneic transplantation of NSUN2-knockdown KPC cells via subcutaneous injection showed decreased stromal fibrosis and restored differentiation of ductal epithelium in vivo.
Significance
Transcriptome-wide mRNA bisulfite sequencing identified candidate m
5
C sites of mRNAs in human pancreatic cancer cells.
NSUN2-mediated m
5
C mRNA metabolism was observed in a mouse model of pancreatic cancer.
NSUN2 regulates cancer progression and epithelial differentiation via mRNA methylation. |
| doi_str_mv | 10.1038/s41388-022-02325-7 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2669793716</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2669793716</sourcerecordid><originalsourceid>FETCH-LOGICAL-c305t-449c69bf5fe4de71854b0903a35c728e1484174595058fefa138837d0d1a12223</originalsourceid><addsrcrecordid>eNp9kE1LAzEQhoMotlb_gAcJeF7N52ZzLOIXlApqz2G7O6kpbXZNdgX_valb9eZhyIT3nXeYB6FzSq4o4cV1FJQXRUYYS8WZzNQBGlOh8kxKLQ7RmGhJMp2kETqJcU0IUZqwYzTiUhIqcjJG_nk-xUsX-411HeAI7z34yvkVDvAB5Sbi-ctizrIt1K7soMaxb9sAMbrG48ZiaF33BhtXbnDtrIUAvkvGneo8bktfBUjfClephXCKjmwKhbP9O0GLu9vXm4ds9nT_eDOdZRUnssuE0FWul1ZaEDUoWkixJJrwkstKsQKoKARVQqb7ZGHBljsQXNWkpiVljPEJuhxy29Cki2Jn1k0ffFppWJ5rpbmieXKxwVWFJsYA1rTBbcvwaSgxO8RmQGwSYvON2Kg0dLGP7peJyu_ID9Nk4IMhJsmvIPzt_if2C_NDhu8</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2669793716</pqid></control><display><type>article</type><title>RNA bisulfite sequencing reveals NSUN2-mediated suppression of epithelial differentiation in pancreatic cancer</title><source>MEDLINE</source><source>SpringerLink Journals</source><creator>Chen, Szu-Ying ; Chen, Kuan-Lin ; Ding, Li-Yun ; Yu, Chien-Hung ; Wu, Hsin-Yi ; Chou, Ya-Yi ; Chang, Chia-Jung ; Chang, Chih-Han ; Wu, Ya-Na ; Wu, Shang-Rung ; Hou, Ya-Chin ; Lee, Chung-Ta ; Chen, Peng-Chieh ; Shan, Yan-Shen ; Huang, Po-Hsien</creator><creatorcontrib>Chen, Szu-Ying ; Chen, Kuan-Lin ; Ding, Li-Yun ; Yu, Chien-Hung ; Wu, Hsin-Yi ; Chou, Ya-Yi ; Chang, Chia-Jung ; Chang, Chih-Han ; Wu, Ya-Na ; Wu, Shang-Rung ; Hou, Ya-Chin ; Lee, Chung-Ta ; Chen, Peng-Chieh ; Shan, Yan-Shen ; Huang, Po-Hsien</creatorcontrib><description>Posttranscriptional modifications in RNA have been considered to contribute to disease pathogenesis and tumor progression. NOL1/NOP2/Sun domain family member 2 (NSUN2) is an RNA methyltransferase that promotes tumor progression in several cancers. Pancreatic cancer relapse inevitably occurs even in cases where primary tumors have been successfully treated. Associations of cancer progression due to reprogramming of the cancer methyl-metabolome and the cancer genome have been noted, but the effect of base modifications, namely 5-methylcytosine (m
5
C), in the transcriptome remains unclear. Aberrant regulation of 5-methylcytosine turnover in cancer may affect posttranscriptional modifications in coding and noncoding RNAs in disease pathogenesis. Mutations in NSUN2 have been reported as drivers of neurodevelopmental disorders in mice, and upregulated expression of NSUN2 in tumors of the breast, bladder, and pancreas has been reported. In this study, we conducted mRNA whole transcriptomic bisulfite sequencing to categorize NSUN2 target sites in the mRNA of human pancreatic cancer cells. We identified a total of 2829 frequent m
5
C sites in mRNA from pancreatic cancer cells. A total of 90.9% (2572/2829) of these m
5
C sites were mapped to annotated genes in autosomes and sex chromosomes X and Y. Immunohistochemistry staining confirmed that the NSUN2 expression was significantly upregulated in cancer lesions in the
LSL-Kras
G12D/+
;Trp53
fl/fl
;Pdx1-Cre
(KPC) spontaneous pancreatic cancer mouse model induced by Pdx1-driven Cre/lox system expressing mutant Kras
G12D
and p53 deletion. The in vitro phenotypic analysis of NSUN2 knockdown showed mild effects on pancreatic cancer cell 2D/3D growth, morphology and gemcitabine sensitivity in the early phase of tumorigenesis, but cumulative changes after multiple cell doubling passages over time were required for these mutations to accumulate. Syngeneic transplantation of NSUN2-knockdown KPC cells via subcutaneous injection showed decreased stromal fibrosis and restored differentiation of ductal epithelium in vivo.
Significance
Transcriptome-wide mRNA bisulfite sequencing identified candidate m
5
C sites of mRNAs in human pancreatic cancer cells.
NSUN2-mediated m
5
C mRNA metabolism was observed in a mouse model of pancreatic cancer.
NSUN2 regulates cancer progression and epithelial differentiation via mRNA methylation.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-022-02325-7</identifier><identifier>PMID: 35501460</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>101/28 ; 13/105 ; 13/51 ; 38/91 ; 45/90 ; 5-Methylcytosine ; 631/1647/514 ; 631/208/177 ; 631/337/1427/2122 ; 631/61/391 ; 631/67/1504/1713 ; 64/110 ; 82/58 ; 96/1 ; Animals ; Apoptosis ; Bisulfite ; Breast ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - pathology ; Cell Biology ; Cell Transformation, Neoplastic - genetics ; Cytology ; Disease Models, Animal ; Epithelium ; Fibrosis ; Gemcitabine ; Genomes ; Human Genetics ; Humans ; Immunohistochemistry ; Internal Medicine ; Medicine ; Medicine & Public Health ; Methyltransferases - metabolism ; Mice ; Mutation ; Neurodevelopmental disorders ; Non-coding RNA ; Oncology ; p53 Protein ; Pancreatic cancer ; Pancreatic Neoplasms ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - pathology ; Pathogenesis ; Post-transcription ; Proto-Oncogene Proteins p21(ras) - metabolism ; RNA ; RNA, Messenger - genetics ; Sex chromosomes ; Sulfites ; Transcriptomes ; Transcriptomics ; Transplantation ; Tumorigenesis ; Tumors</subject><ispartof>Oncogene, 2022-05, Vol.41 (22), p.3162-3176</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2022</rights><rights>2022. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2022.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c305t-449c69bf5fe4de71854b0903a35c728e1484174595058fefa138837d0d1a12223</citedby><cites>FETCH-LOGICAL-c305t-449c69bf5fe4de71854b0903a35c728e1484174595058fefa138837d0d1a12223</cites><orcidid>0000-0003-1387-1596 ; 0000-0003-3576-2921 ; 0000-0002-2997-5181 ; 0000-0002-3998-5922 ; 0000-0002-2457-5189 ; 0000-0003-0977-8743</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41388-022-02325-7$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-022-02325-7$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35501460$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Szu-Ying</creatorcontrib><creatorcontrib>Chen, Kuan-Lin</creatorcontrib><creatorcontrib>Ding, Li-Yun</creatorcontrib><creatorcontrib>Yu, Chien-Hung</creatorcontrib><creatorcontrib>Wu, Hsin-Yi</creatorcontrib><creatorcontrib>Chou, Ya-Yi</creatorcontrib><creatorcontrib>Chang, Chia-Jung</creatorcontrib><creatorcontrib>Chang, Chih-Han</creatorcontrib><creatorcontrib>Wu, Ya-Na</creatorcontrib><creatorcontrib>Wu, Shang-Rung</creatorcontrib><creatorcontrib>Hou, Ya-Chin</creatorcontrib><creatorcontrib>Lee, Chung-Ta</creatorcontrib><creatorcontrib>Chen, Peng-Chieh</creatorcontrib><creatorcontrib>Shan, Yan-Shen</creatorcontrib><creatorcontrib>Huang, Po-Hsien</creatorcontrib><title>RNA bisulfite sequencing reveals NSUN2-mediated suppression of epithelial differentiation in pancreatic cancer</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Posttranscriptional modifications in RNA have been considered to contribute to disease pathogenesis and tumor progression. NOL1/NOP2/Sun domain family member 2 (NSUN2) is an RNA methyltransferase that promotes tumor progression in several cancers. Pancreatic cancer relapse inevitably occurs even in cases where primary tumors have been successfully treated. Associations of cancer progression due to reprogramming of the cancer methyl-metabolome and the cancer genome have been noted, but the effect of base modifications, namely 5-methylcytosine (m
5
C), in the transcriptome remains unclear. Aberrant regulation of 5-methylcytosine turnover in cancer may affect posttranscriptional modifications in coding and noncoding RNAs in disease pathogenesis. Mutations in NSUN2 have been reported as drivers of neurodevelopmental disorders in mice, and upregulated expression of NSUN2 in tumors of the breast, bladder, and pancreas has been reported. In this study, we conducted mRNA whole transcriptomic bisulfite sequencing to categorize NSUN2 target sites in the mRNA of human pancreatic cancer cells. We identified a total of 2829 frequent m
5
C sites in mRNA from pancreatic cancer cells. A total of 90.9% (2572/2829) of these m
5
C sites were mapped to annotated genes in autosomes and sex chromosomes X and Y. Immunohistochemistry staining confirmed that the NSUN2 expression was significantly upregulated in cancer lesions in the
LSL-Kras
G12D/+
;Trp53
fl/fl
;Pdx1-Cre
(KPC) spontaneous pancreatic cancer mouse model induced by Pdx1-driven Cre/lox system expressing mutant Kras
G12D
and p53 deletion. The in vitro phenotypic analysis of NSUN2 knockdown showed mild effects on pancreatic cancer cell 2D/3D growth, morphology and gemcitabine sensitivity in the early phase of tumorigenesis, but cumulative changes after multiple cell doubling passages over time were required for these mutations to accumulate. Syngeneic transplantation of NSUN2-knockdown KPC cells via subcutaneous injection showed decreased stromal fibrosis and restored differentiation of ductal epithelium in vivo.
Significance
Transcriptome-wide mRNA bisulfite sequencing identified candidate m
5
C sites of mRNAs in human pancreatic cancer cells.
NSUN2-mediated m
5
C mRNA metabolism was observed in a mouse model of pancreatic cancer.
NSUN2 regulates cancer progression and epithelial differentiation via mRNA methylation.</description><subject>101/28</subject><subject>13/105</subject><subject>13/51</subject><subject>38/91</subject><subject>45/90</subject><subject>5-Methylcytosine</subject><subject>631/1647/514</subject><subject>631/208/177</subject><subject>631/337/1427/2122</subject><subject>631/61/391</subject><subject>631/67/1504/1713</subject><subject>64/110</subject><subject>82/58</subject><subject>96/1</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Bisulfite</subject><subject>Breast</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cell Biology</subject><subject>Cell Transformation, Neoplastic - genetics</subject><subject>Cytology</subject><subject>Disease Models, Animal</subject><subject>Epithelium</subject><subject>Fibrosis</subject><subject>Gemcitabine</subject><subject>Genomes</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Internal Medicine</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Methyltransferases - metabolism</subject><subject>Mice</subject><subject>Mutation</subject><subject>Neurodevelopmental disorders</subject><subject>Non-coding RNA</subject><subject>Oncology</subject><subject>p53 Protein</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Pathogenesis</subject><subject>Post-transcription</subject><subject>Proto-Oncogene Proteins p21(ras) - metabolism</subject><subject>RNA</subject><subject>RNA, Messenger - genetics</subject><subject>Sex chromosomes</subject><subject>Sulfites</subject><subject>Transcriptomes</subject><subject>Transcriptomics</subject><subject>Transplantation</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kE1LAzEQhoMotlb_gAcJeF7N52ZzLOIXlApqz2G7O6kpbXZNdgX_valb9eZhyIT3nXeYB6FzSq4o4cV1FJQXRUYYS8WZzNQBGlOh8kxKLQ7RmGhJMp2kETqJcU0IUZqwYzTiUhIqcjJG_nk-xUsX-411HeAI7z34yvkVDvAB5Sbi-ctizrIt1K7soMaxb9sAMbrG48ZiaF33BhtXbnDtrIUAvkvGneo8bktfBUjfClephXCKjmwKhbP9O0GLu9vXm4ds9nT_eDOdZRUnssuE0FWul1ZaEDUoWkixJJrwkstKsQKoKARVQqb7ZGHBljsQXNWkpiVljPEJuhxy29Cki2Jn1k0ffFppWJ5rpbmieXKxwVWFJsYA1rTBbcvwaSgxO8RmQGwSYvON2Kg0dLGP7peJyu_ID9Nk4IMhJsmvIPzt_if2C_NDhu8</recordid><startdate>20220527</startdate><enddate>20220527</enddate><creator>Chen, Szu-Ying</creator><creator>Chen, Kuan-Lin</creator><creator>Ding, Li-Yun</creator><creator>Yu, Chien-Hung</creator><creator>Wu, Hsin-Yi</creator><creator>Chou, Ya-Yi</creator><creator>Chang, Chia-Jung</creator><creator>Chang, Chih-Han</creator><creator>Wu, Ya-Na</creator><creator>Wu, Shang-Rung</creator><creator>Hou, Ya-Chin</creator><creator>Lee, Chung-Ta</creator><creator>Chen, Peng-Chieh</creator><creator>Shan, Yan-Shen</creator><creator>Huang, Po-Hsien</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0003-1387-1596</orcidid><orcidid>https://orcid.org/0000-0003-3576-2921</orcidid><orcidid>https://orcid.org/0000-0002-2997-5181</orcidid><orcidid>https://orcid.org/0000-0002-3998-5922</orcidid><orcidid>https://orcid.org/0000-0002-2457-5189</orcidid><orcidid>https://orcid.org/0000-0003-0977-8743</orcidid></search><sort><creationdate>20220527</creationdate><title>RNA bisulfite sequencing reveals NSUN2-mediated suppression of epithelial differentiation in pancreatic cancer</title><author>Chen, Szu-Ying ; Chen, Kuan-Lin ; Ding, Li-Yun ; Yu, Chien-Hung ; Wu, Hsin-Yi ; Chou, Ya-Yi ; Chang, Chia-Jung ; Chang, Chih-Han ; Wu, Ya-Na ; Wu, Shang-Rung ; Hou, Ya-Chin ; Lee, Chung-Ta ; Chen, Peng-Chieh ; Shan, Yan-Shen ; Huang, Po-Hsien</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c305t-449c69bf5fe4de71854b0903a35c728e1484174595058fefa138837d0d1a12223</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>101/28</topic><topic>13/105</topic><topic>13/51</topic><topic>38/91</topic><topic>45/90</topic><topic>5-Methylcytosine</topic><topic>631/1647/514</topic><topic>631/208/177</topic><topic>631/337/1427/2122</topic><topic>631/61/391</topic><topic>631/67/1504/1713</topic><topic>64/110</topic><topic>82/58</topic><topic>96/1</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Bisulfite</topic><topic>Breast</topic><topic>Carcinoma, Pancreatic Ductal - genetics</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>Cell Biology</topic><topic>Cell Transformation, Neoplastic - genetics</topic><topic>Cytology</topic><topic>Disease Models, Animal</topic><topic>Epithelium</topic><topic>Fibrosis</topic><topic>Gemcitabine</topic><topic>Genomes</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Internal Medicine</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Methyltransferases - metabolism</topic><topic>Mice</topic><topic>Mutation</topic><topic>Neurodevelopmental disorders</topic><topic>Non-coding RNA</topic><topic>Oncology</topic><topic>p53 Protein</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Pathogenesis</topic><topic>Post-transcription</topic><topic>Proto-Oncogene Proteins p21(ras) - metabolism</topic><topic>RNA</topic><topic>RNA, Messenger - genetics</topic><topic>Sex chromosomes</topic><topic>Sulfites</topic><topic>Transcriptomes</topic><topic>Transcriptomics</topic><topic>Transplantation</topic><topic>Tumorigenesis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Szu-Ying</creatorcontrib><creatorcontrib>Chen, Kuan-Lin</creatorcontrib><creatorcontrib>Ding, Li-Yun</creatorcontrib><creatorcontrib>Yu, Chien-Hung</creatorcontrib><creatorcontrib>Wu, Hsin-Yi</creatorcontrib><creatorcontrib>Chou, Ya-Yi</creatorcontrib><creatorcontrib>Chang, Chia-Jung</creatorcontrib><creatorcontrib>Chang, Chih-Han</creatorcontrib><creatorcontrib>Wu, Ya-Na</creatorcontrib><creatorcontrib>Wu, Shang-Rung</creatorcontrib><creatorcontrib>Hou, Ya-Chin</creatorcontrib><creatorcontrib>Lee, Chung-Ta</creatorcontrib><creatorcontrib>Chen, Peng-Chieh</creatorcontrib><creatorcontrib>Shan, Yan-Shen</creatorcontrib><creatorcontrib>Huang, Po-Hsien</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Szu-Ying</au><au>Chen, Kuan-Lin</au><au>Ding, Li-Yun</au><au>Yu, Chien-Hung</au><au>Wu, Hsin-Yi</au><au>Chou, Ya-Yi</au><au>Chang, Chia-Jung</au><au>Chang, Chih-Han</au><au>Wu, Ya-Na</au><au>Wu, Shang-Rung</au><au>Hou, Ya-Chin</au><au>Lee, Chung-Ta</au><au>Chen, Peng-Chieh</au><au>Shan, Yan-Shen</au><au>Huang, Po-Hsien</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RNA bisulfite sequencing reveals NSUN2-mediated suppression of epithelial differentiation in pancreatic cancer</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2022-05-27</date><risdate>2022</risdate><volume>41</volume><issue>22</issue><spage>3162</spage><epage>3176</epage><pages>3162-3176</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Posttranscriptional modifications in RNA have been considered to contribute to disease pathogenesis and tumor progression. NOL1/NOP2/Sun domain family member 2 (NSUN2) is an RNA methyltransferase that promotes tumor progression in several cancers. Pancreatic cancer relapse inevitably occurs even in cases where primary tumors have been successfully treated. Associations of cancer progression due to reprogramming of the cancer methyl-metabolome and the cancer genome have been noted, but the effect of base modifications, namely 5-methylcytosine (m
5
C), in the transcriptome remains unclear. Aberrant regulation of 5-methylcytosine turnover in cancer may affect posttranscriptional modifications in coding and noncoding RNAs in disease pathogenesis. Mutations in NSUN2 have been reported as drivers of neurodevelopmental disorders in mice, and upregulated expression of NSUN2 in tumors of the breast, bladder, and pancreas has been reported. In this study, we conducted mRNA whole transcriptomic bisulfite sequencing to categorize NSUN2 target sites in the mRNA of human pancreatic cancer cells. We identified a total of 2829 frequent m
5
C sites in mRNA from pancreatic cancer cells. A total of 90.9% (2572/2829) of these m
5
C sites were mapped to annotated genes in autosomes and sex chromosomes X and Y. Immunohistochemistry staining confirmed that the NSUN2 expression was significantly upregulated in cancer lesions in the
LSL-Kras
G12D/+
;Trp53
fl/fl
;Pdx1-Cre
(KPC) spontaneous pancreatic cancer mouse model induced by Pdx1-driven Cre/lox system expressing mutant Kras
G12D
and p53 deletion. The in vitro phenotypic analysis of NSUN2 knockdown showed mild effects on pancreatic cancer cell 2D/3D growth, morphology and gemcitabine sensitivity in the early phase of tumorigenesis, but cumulative changes after multiple cell doubling passages over time were required for these mutations to accumulate. Syngeneic transplantation of NSUN2-knockdown KPC cells via subcutaneous injection showed decreased stromal fibrosis and restored differentiation of ductal epithelium in vivo.
Significance
Transcriptome-wide mRNA bisulfite sequencing identified candidate m
5
C sites of mRNAs in human pancreatic cancer cells.
NSUN2-mediated m
5
C mRNA metabolism was observed in a mouse model of pancreatic cancer.
NSUN2 regulates cancer progression and epithelial differentiation via mRNA methylation.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>35501460</pmid><doi>10.1038/s41388-022-02325-7</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0003-1387-1596</orcidid><orcidid>https://orcid.org/0000-0003-3576-2921</orcidid><orcidid>https://orcid.org/0000-0002-2997-5181</orcidid><orcidid>https://orcid.org/0000-0002-3998-5922</orcidid><orcidid>https://orcid.org/0000-0002-2457-5189</orcidid><orcidid>https://orcid.org/0000-0003-0977-8743</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2022-05, Vol.41 (22), p.3162-3176 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_proquest_journals_2669793716 |
| source | MEDLINE; SpringerLink Journals |
| subjects | 101/28 13/105 13/51 38/91 45/90 5-Methylcytosine 631/1647/514 631/208/177 631/337/1427/2122 631/61/391 631/67/1504/1713 64/110 82/58 96/1 Animals Apoptosis Bisulfite Breast Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - pathology Cell Biology Cell Transformation, Neoplastic - genetics Cytology Disease Models, Animal Epithelium Fibrosis Gemcitabine Genomes Human Genetics Humans Immunohistochemistry Internal Medicine Medicine Medicine & Public Health Methyltransferases - metabolism Mice Mutation Neurodevelopmental disorders Non-coding RNA Oncology p53 Protein Pancreatic cancer Pancreatic Neoplasms Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Pathogenesis Post-transcription Proto-Oncogene Proteins p21(ras) - metabolism RNA RNA, Messenger - genetics Sex chromosomes Sulfites Transcriptomes Transcriptomics Transplantation Tumorigenesis Tumors |
| title | RNA bisulfite sequencing reveals NSUN2-mediated suppression of epithelial differentiation in pancreatic cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T06%3A33%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=RNA%20bisulfite%20sequencing%20reveals%20NSUN2-mediated%20suppression%20of%20epithelial%20differentiation%20in%20pancreatic%20cancer&rft.jtitle=Oncogene&rft.au=Chen,%20Szu-Ying&rft.date=2022-05-27&rft.volume=41&rft.issue=22&rft.spage=3162&rft.epage=3176&rft.pages=3162-3176&rft.issn=0950-9232&rft.eissn=1476-5594&rft_id=info:doi/10.1038/s41388-022-02325-7&rft_dat=%3Cproquest_cross%3E2669793716%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2669793716&rft_id=info:pmid/35501460&rfr_iscdi=true |