Brain-derived neurotrophic factor involved epigenetic repression of UGT2B7 in colorectal carcinoma: A mechanism to alter morphine glucuronidation in tumor

Zi-Zhao Yang; Li Li; Ming-Cheng Xu; Hai-Xing Ju; Miao Hao; Jing-Kai Gu; Zai-Jie Jim Wang; Hui-Di Jiang; Lu-Shan Yu; Su Zeng

doi:10.18632/oncotarget.16251

Brain-derived neurotrophic factor involved epigenetic repression of UGT2B7 in colorectal carcinoma: A mechanism to alter morphine glucuronidation in tumor

Oncotarget. 2017 Apr 25;8(17):29138-29150. doi: 10.18632/oncotarget.16251.

Authors

Zi-Zhao Yang¹, Li Li², Ming-Cheng Xu¹, Hai-Xing Ju³, Miao Hao⁴, Jing-Kai Gu⁵, Zai-Jie Jim Wang⁶, Hui-Di Jiang¹, Lu-Shan Yu¹, Su Zeng¹

Affiliations

¹ 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.
² Department of Pharmacy, Zhejiang Hospital, Zhejiang Provincial Key Lab of Geriatrics, Hangzhou 310013, China.
³ Department of Colorectal Surgery, Zhejiang Provincial Tumor Hospital, Hangzhou, 310022, China.
⁴ Science Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, China.
⁵ School of Life Sciences, Jilin University, Changchun, 130012, China.
⁶ Department of Biopharmaceutical Sciences and Cancer Center, University of Illinois at Chicago, Chicago, Illinois 60612, USA.

Abstract

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.

Keywords: BDNF; UGT2B7; colorectal carcinoma; epigenetics; morphine tolerance.

MeSH terms

Adult
Aged
Aged, 80 and over
Analgesics, Opioid / pharmacology*
Analgesics, Opioid / therapeutic use
Azepines / pharmacology
Brain-Derived Neurotrophic Factor / genetics
Brain-Derived Neurotrophic Factor / metabolism*
Cancer Pain / drug therapy
Cell Line, Tumor
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / pathology
Drug Tolerance / genetics
Epigenetic Repression*
Female
Gene Expression Regulation, Neoplastic*
Gene Knockdown Techniques
Glucuronosyltransferase / genetics*
Glucuronosyltransferase / metabolism
Histocompatibility Antigens / metabolism
Histone-Lysine N-Methyltransferase / antagonists & inhibitors
Histone-Lysine N-Methyltransferase / metabolism
Histones / metabolism
Humans
Immunohistochemistry
Male
Middle Aged
Morphine / pharmacology
Morphine / therapeutic use
Morphine Derivatives / metabolism
Neoplasm Proteins
Polycomb Repressive Complex 1 / metabolism
Polycomb Repressive Complex 2 / metabolism
Promoter Regions, Genetic / genetics
Quinazolines / pharmacology
RNA Interference
RNA, Small Interfering / metabolism
Transcription Factors
Up-Regulation

Substances

Analgesics, Opioid
Azepines
BIX 01294
Brain-Derived Neurotrophic Factor
Histocompatibility Antigens
Histones
Morphine Derivatives
Neoplasm Proteins
Quinazolines
RNA, Small Interfering
SUZ12 protein, human
Transcription Factors
morphine-6-glucuronide
BDNF protein, human
Morphine
EHMT2 protein, human
Histone-Lysine N-Methyltransferase
Polycomb Repressive Complex 2
Polycomb Repressive Complex 1
UGT2B7 protein, human
Glucuronosyltransferase
morphine-3-glucuronide