PMID- 28418861 OWN - NLM STAT- MEDLINE DCOM- 20180309 LR - 20211204 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 8 IP - 17 DP - 2017 Apr 25 TI - Brain-derived neurotrophic factor involved epigenetic repression of UGT2B7 in colorectal carcinoma: A mechanism to alter morphine glucuronidation in tumor. PG - 29138-29150 LID - 10.18632/oncotarget.16251 [doi] AB - Uridine diphosphate-glucuronosyltransferase (UGT) 2B7, as one of significant drug enzymes, is responsible on the glucuronidation of abundant endobiotics or xenobiotics. We here report that it is markedly repressed in the tumor tissues of colorectal carcinoma (CRC) patients. Accordingly, morphine in CRC cells will stimulate the expression of its main metabolic enzyme, UGT2B7 during tolerance generation by activating the positive signals in histone 3, especially for trimethylated lysine 27 (H3K4Me3) and acetylated lysine 4 (H3K27Ac). Further study reveals that brain-derived neutrophilic factor (BDNF), a secretory neurotrophin, enriched in CRC can interact and inhibit UGT2B7 by primarily blocking the positive signals of H3K4Me3 as well as activating H3K27Ac on the promoter region of UGT2B7. Meanwhile, BDNF repression attributes to the sensitizations of main core factors in poly-comb repressive complex (PRC) 1 rather than PRC2 as the reason of the depression of SUZ12 in the later complex. Besides that, the productions of two main morphine glucuronides are both increased in the BDNF deficient or TSA and BIX-01294 treated morphine tolerance-like HCT-116 cells. On the same condition, active metabolite, morphine-6-glucuronide (M6G) was accumulated more than inactive M3G. Our findings imply that enzymatic activity enhancement and substrate regioselective catalysis alteration of UGT2B7 may release morphine tolerance under the cure of tumor-induced pain. FAU - Yang, Zi-Zhao AU - Yang ZZ AD - Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Li, Li AU - Li L AD - Department of Pharmacy, Zhejiang Hospital, Zhejiang Provincial Key Lab of Geriatrics, Hangzhou 310013, China. FAU - Xu, Ming-Cheng AU - Xu MC AD - Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Ju, Hai-Xing AU - Ju HX AD - Department of Colorectal Surgery, Zhejiang Provincial Tumor Hospital, Hangzhou, 310022, China. FAU - Hao, Miao AU - Hao M AD - Science Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, China. FAU - Gu, Jing-Kai AU - Gu JK AD - School of Life Sciences, Jilin University, Changchun, 130012, China. FAU - Jim Wang, Zai-Jie AU - Jim Wang ZJ AD - Department of Biopharmaceutical Sciences and Cancer Center, University of Illinois at Chicago, Chicago, Illinois 60612, USA. FAU - Jiang, Hui-Di AU - Jiang HD AD - Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Yu, Lu-Shan AU - Yu LS AD - Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. FAU - Zeng, Su AU - Zeng S AD - Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. LA - eng PT - Journal Article PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (Analgesics, Opioid) RN - 0 (Azepines) RN - 0 (BIX 01294) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Histocompatibility Antigens) RN - 0 (Histones) RN - 0 (Morphine Derivatives) RN - 0 (Neoplasm Proteins) RN - 0 (Quinazolines) RN - 0 (RNA, Small Interfering) RN - 0 (SUZ12 protein, human) RN - 0 (Transcription Factors) RN - 64Y9KYM60R (morphine-6-glucuronide) RN - 7171WSG8A2 (BDNF protein, human) RN - 76I7G6D29C (Morphine) RN - EC 2.1.1.43 (EHMT2 protein, human) RN - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) RN - EC 2.1.1.43 (Polycomb Repressive Complex 2) RN - EC 2.3.2.27 (Polycomb Repressive Complex 1) RN - EC 2.4.1.- (UGT2B7 protein, human) RN - EC 2.4.1.17 (Glucuronosyltransferase) RN - O27Z9CH39A (morphine-3-glucuronide) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Analgesics, Opioid/*pharmacology/therapeutic use MH - Azepines/pharmacology MH - Brain-Derived Neurotrophic Factor/genetics/*metabolism MH - Cancer Pain/drug therapy MH - Cell Line, Tumor MH - Colorectal Neoplasms/*genetics/pathology MH - Drug Tolerance/genetics MH - *Epigenetic Repression MH - Female MH - *Gene Expression Regulation, Neoplastic MH - Gene Knockdown Techniques MH - Glucuronosyltransferase/*genetics/metabolism MH - Histocompatibility Antigens/metabolism MH - Histone-Lysine N-Methyltransferase/antagonists & inhibitors/metabolism MH - Histones/metabolism MH - Humans MH - Immunohistochemistry MH - Male MH - Middle Aged MH - Morphine/pharmacology/therapeutic use MH - Morphine Derivatives/metabolism MH - Neoplasm Proteins MH - Polycomb Repressive Complex 1/metabolism MH - Polycomb Repressive Complex 2/metabolism MH - Promoter Regions, Genetic/genetics MH - Quinazolines/pharmacology MH - RNA Interference MH - RNA, Small Interfering/metabolism MH - Transcription Factors MH - Up-Regulation PMC - PMC5438719 OTO - NOTNLM OT - BDNF OT - UGT2B7 OT - colorectal carcinoma OT - epigenetics OT - morphine tolerance COIS- CONFLICTS OF INTEREST The authors declare no conflicts of interest. EDAT- 2017/04/19 06:00 MHDA- 2018/03/10 06:00 PMCR- 2017/04/25 CRDT- 2017/04/19 06:00 PHST- 2017/01/10 00:00 [received] PHST- 2017/02/20 00:00 [accepted] PHST- 2017/04/19 06:00 [pubmed] PHST- 2018/03/10 06:00 [medline] PHST- 2017/04/19 06:00 [entrez] PHST- 2017/04/25 00:00 [pmc-release] AID - 16251 [pii] AID - 10.18632/oncotarget.16251 [doi] PST - ppublish SO - Oncotarget. 2017 Apr 25;8(17):29138-29150. doi: 10.18632/oncotarget.16251.