MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription
Identifieur interne : 000241 ( an2020/Analysis ); précédent : 000240; suivant : 000242MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription
Auteurs : Tingting Liu [République populaire de Chine] ; Yumin Han [République populaire de Chine] ; Chunhong Yu [République populaire de Chine] ; Yan Ji [République populaire de Chine] ; Changxu Wang [République populaire de Chine] ; Xiaomin Chen [République populaire de Chine] ; Xiang Wang [République populaire de Chine] ; Jiayan Shen [République populaire de Chine] ; Yongfeng Zhang [République populaire de Chine] ; Jing-Yu Lang [République populaire de Chine]Source :
- EBioMedicine [ 2352-3964 ] ; 2019.
Abstract
Thymidylate synthase (TYMS) is a successful chemotherapeutic target for anticancer therapy. Numerous TYMS inhibitors have been developed and used for treating gastrointestinal cancer now, but they have limited clinical benefits due to the prevalent unresponsiveness and toxicity. It is urgent to identify a predictive biomarker to guide the precise clinical use of TYMS inhibitors.
Genome-scale CRISPR-Cas9 knockout screening was performed to identify potential therapeutic targets for treating gastrointestinal tumours as well as key regulators of raltitrexed (RTX) sensitivity. Cell-based functional assays were used to investigate how MYC regulates
TYMS is essential for maintaining the viability of gastrointestinal cancer cells, and is selectively inhibited by RTX. Mechanistically, MYC presets gastrointestinal cancer sensitivity to RTX through upregulating
Our study unveils a mechanism of how
This work was financially supported by grants of
Url:
DOI: 10.1016/j.ebiom.2019.10.003
PubMed: 31648989
PubMed Central: 6838448
Affiliations:
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PMC:6838448Le document en format XML
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last="Shen">Jiayan Shen</name><affiliation wicri:level="1"><nlm:aff id="aff0001">The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Yongfeng" sort="Zhang, Yongfeng" uniqKey="Zhang Y" first="Yongfeng" last="Zhang">Yongfeng Zhang</name><affiliation wicri:level="1"><nlm:aff id="aff0001">The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author><author><name sortKey="Lang, Jing Yu" sort="Lang, Jing Yu" uniqKey="Lang J" first="Jing-Yu" last="Lang">Jing-Yu Lang</name><affiliation wicri:level="1"><nlm:aff id="aff0001">The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country 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Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author><author><name sortKey="Han, Yumin" sort="Han, Yumin" uniqKey="Han Y" first="Yumin" last="Han">Yumin Han</name><affiliation wicri:level="1"><nlm:aff id="aff0001">The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author><author><name sortKey="Yu, Chunhong" sort="Yu, Chunhong" uniqKey="Yu C" first="Chunhong" last="Yu">Chunhong Yu</name><affiliation wicri:level="1"><nlm:aff id="aff0001">The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author><author><name sortKey="Ji, Yan" sort="Ji, Yan" uniqKey="Ji Y" first="Yan" last="Ji">Yan Ji</name><affiliation wicri:level="1"><nlm:aff id="aff0002">Bioinformatics Core, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Bioinformatics Core, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Changxu" sort="Wang, Changxu" uniqKey="Wang C" first="Changxu" last="Wang">Changxu Wang</name><affiliation wicri:level="1"><nlm:aff id="aff0001">The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Xiaomin" sort="Chen, Xiaomin" uniqKey="Chen X" first="Xiaomin" last="Chen">Xiaomin Chen</name><affiliation wicri:level="1"><nlm:aff id="aff0001">The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author><author><name sortKey="Wang, Xiang" sort="Wang, Xiang" uniqKey="Wang X" first="Xiang" last="Wang">Xiang Wang</name><affiliation wicri:level="1"><nlm:aff id="aff0001">The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author><author><name sortKey="Shen, Jiayan" sort="Shen, Jiayan" uniqKey="Shen J" first="Jiayan" last="Shen">Jiayan Shen</name><affiliation wicri:level="1"><nlm:aff id="aff0001">The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Yongfeng" sort="Zhang, Yongfeng" uniqKey="Zhang Y" first="Yongfeng" last="Zhang">Yongfeng Zhang</name><affiliation wicri:level="1"><nlm:aff id="aff0001">The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author><author><name sortKey="Lang, Jing Yu" sort="Lang, Jing Yu" uniqKey="Lang J" first="Jing-Yu" last="Lang">Jing-Yu Lang</name><affiliation wicri:level="1"><nlm:aff id="aff0001">The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The CAS_Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031</wicri:regionArea><wicri:noRegion>Shanghai 200031</wicri:noRegion></affiliation></author></analytic><series><title level="j">EBioMedicine</title><idno type="eISSN">2352-3964</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Thymidylate synthase (TYMS) is a successful chemotherapeutic target for anticancer therapy. Numerous TYMS inhibitors have been developed and used for treating gastrointestinal cancer now, but they have limited clinical benefits due to the prevalent unresponsiveness and toxicity. It is urgent to identify a predictive biomarker to guide the precise clinical use of TYMS inhibitors.</p></sec><sec><title>Methods</title><p>Genome-scale CRISPR-Cas9 knockout screening was performed to identify potential therapeutic targets for treating gastrointestinal tumours as well as key regulators of raltitrexed (RTX) sensitivity. Cell-based functional assays were used to investigate how MYC regulates <italic>TYMS</italic> transcription. Cancer patient data were used to verify the correlation between drug response and MYC and/or TYMS mRNA levels. Finally, the role of NIPBL inactivation in gastrointestinal cancer was evaluated <italic>in vitro</italic> and <italic>in vivo</italic>.</p></sec><sec><title>Findings</title><p>TYMS is essential for maintaining the viability of gastrointestinal cancer cells, and is selectively inhibited by RTX. Mechanistically, MYC presets gastrointestinal cancer sensitivity to RTX through upregulating <italic>TYMS</italic> transcription, supported by TCGA data showing that complete response cases to TYMS inhibitors had significantly higher MYC and TYMS mRNA levels than those of progressive diseases. NIPBL inactivation decreases the therapeutic responses of gastrointestinal cancer to RTX through blocking MYC.</p></sec><sec><title>Interpretation</title><p>Our study unveils a mechanism of how <italic>TYMS</italic> is transcriptionally regulated by MYC, and provides rationales for the precise use of TYMS inhibitors in the clinic.</p></sec><sec><title>Funding</title><p>This work was financially supported by grants of <funding-source id="gs0001">NKRDP</funding-source> (2016YFC1302400), <funding-source id="gs0002">STCSM</funding-source> (16JC1406200), <funding-source id="gs0003">NSFC</funding-source> (81872890, 81322034, 81372346) and <funding-source id="gs0004">CAS</funding-source> (QYZDB-SSW-SMC034, XDA12020210).</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Graham, D Y" uniqKey="Graham D">D.Y. Graham</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Torre, L A" uniqKey="Torre L">L.A. 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Wang</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>République populaire de Chine</li></country></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Liu, Tingting" sort="Liu, Tingting" uniqKey="Liu T" first="Tingting" last="Liu">Tingting Liu</name></noRegion><name sortKey="Chen, Xiaomin" sort="Chen, Xiaomin" uniqKey="Chen X" first="Xiaomin" last="Chen">Xiaomin Chen</name><name sortKey="Han, Yumin" sort="Han, Yumin" uniqKey="Han Y" first="Yumin" last="Han">Yumin Han</name><name sortKey="Ji, Yan" sort="Ji, Yan" uniqKey="Ji Y" first="Yan" last="Ji">Yan Ji</name><name sortKey="Lang, Jing Yu" sort="Lang, Jing Yu" uniqKey="Lang J" first="Jing-Yu" last="Lang">Jing-Yu Lang</name><name sortKey="Shen, Jiayan" sort="Shen, Jiayan" uniqKey="Shen J" first="Jiayan" last="Shen">Jiayan Shen</name><name sortKey="Wang, Changxu" sort="Wang, Changxu" uniqKey="Wang C" first="Changxu" last="Wang">Changxu Wang</name><name sortKey="Wang, Xiang" sort="Wang, Xiang" uniqKey="Wang X" first="Xiang" last="Wang">Xiang Wang</name><name sortKey="Yu, Chunhong" sort="Yu, Chunhong" uniqKey="Yu C" first="Chunhong" last="Yu">Chunhong Yu</name><name sortKey="Zhang, Yongfeng" sort="Zhang, Yongfeng" uniqKey="Zhang Y" first="Yongfeng" last="Zhang">Yongfeng Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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