PMID- 31648989 OWN - NLM STAT- MEDLINE DCOM- 20200319 LR - 20200319 IS - 2352-3964 (Electronic) IS - 2352-3964 (Linking) VI - 48 DP - 2019 Oct TI - MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription. PG - 289-300 LID - S2352-3964(19)30667-X [pii] LID - 10.1016/j.ebiom.2019.10.003 [doi] AB - BACKGROUND: 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. METHODS: 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 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 in vitro and in vivo. FINDINGS: 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 TYMS 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. INTERPRETATION: Our study unveils a mechanism of how TYMS is transcriptionally regulated by MYC, and provides rationales for the precise use of TYMS inhibitors in the clinic. FUNDING: This work was financially supported by grants of NKRDP (2016YFC1302400), STCSM (16JC1406200), NSFC (81872890, 81322034, 81372346) and CAS (QYZDB-SSW-SMC034, XDA12020210). CI - Copyright (c) 2019. Published by Elsevier B.V. FAU - Liu, Tingting AU - Liu T AD - 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. FAU - Han, Yumin AU - Han Y AD - 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. FAU - Yu, Chunhong AU - Yu C AD - 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. FAU - Ji, Yan AU - Ji Y AD - 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. FAU - Wang, Changxu AU - Wang C AD - 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. FAU - Chen, Xiaomin AU - Chen X AD - 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. FAU - Wang, Xiang AU - Wang X AD - 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. FAU - Shen, Jiayan AU - Shen J AD - 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. FAU - Zhang, Yongfeng AU - Zhang Y AD - 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. FAU - Lang, Jing-Yu AU - Lang JY AD - 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. Electronic address: jylang@sibs.ac.cn. LA - eng PT - Journal Article DEP - 20191021 PL - Netherlands TA - EBioMedicine JT - EBioMedicine JID - 101647039 RN - 0 (Folic Acid Antagonists) RN - EC 2.1.1.45 (TYMS protein, human) RN - EC 2.1.1.45 (Thymidylate Synthase) SB - IM MH - Cell Line, Tumor MH - Dose-Response Relationship, Drug MH - Drug Resistance/*genetics MH - Folic Acid Antagonists/*pharmacology MH - Gastrointestinal Neoplasms/*genetics/metabolism MH - *Gene Expression Regulation, Neoplastic MH - *Genes, myc MH - Humans MH - Thymidylate Synthase/antagonists & inhibitors/*genetics/metabolism MH - Transcription, Genetic PMC - PMC6838448 OTO - NOTNLM OT - Genome-scale CRISPR-Cas9 knockout screening OT - MYC OT - NIPBL OT - Raltitrexed OT - Thymidylate synthase COIS- The authors declare that they have no conflicts of interest. EDAT- 2019/10/28 06:00 MHDA- 2020/03/20 06:00 PMCR- 2019/10/21 CRDT- 2019/10/26 06:00 PHST- 2019/05/05 00:00 [received] PHST- 2019/09/20 00:00 [revised] PHST- 2019/10/01 00:00 [accepted] PHST- 2019/10/28 06:00 [pubmed] PHST- 2020/03/20 06:00 [medline] PHST- 2019/10/26 06:00 [entrez] PHST- 2019/10/21 00:00 [pmc-release] AID - S2352-3964(19)30667-X [pii] AID - 10.1016/j.ebiom.2019.10.003 [doi] PST - ppublish SO - EBioMedicine. 2019 Oct;48:289-300. doi: 10.1016/j.ebiom.2019.10.003. Epub 2019 Oct 21.