title: Loss of MYC and E-box3 binding contributes to defective MYC-mediated transcriptional suppression of human MC-let-7a-1~let-7d in glioblastoma.
abstract: Previously, we reported that MYC oncoprotein down-regulates the transcription of human MC-let-7a-1~let-7d microRNA cluster in hepatocarcinoma (HCC). Surprisingly, in silico analysis indicated that let-7 miRNA expression levels are not reduced in glioblastoma (GBM). Here we investigated the molecular basis of this differential expression. Using human GBM U87 and U251 cells, we first demonstrated that forced over-expression of MYC indeed could not down-regulate the expression of human MC-let-7a-1~let-7d microRNA cluster in GBM. Furthermore, analysis of MC-let-7a-1~let-7d promoter in GBM indicated that MYC failed to inhibit the promoter activity. Pearson's correlation and Linear Regression analysis using the expression data from GSE55092 (HCC) and GSE4290 (GBM) demonstrated a converse relationship of MC-let-7a-1~let-7d and MYC only in HCC but not in GBM. To understand the underlying mechanisms, we examined whether MYC could bind to the non-canonical E-box 3 located in the promoter of MC-let-7a-1~let-7d. Results from both chromatin immune-precipitation (ChIP) and super-shift assays clearly demonstrated the loss of MYC and E-box 3 binding in GBM, suggesting for the first time that a defective MYC and E-box3 binding in GBM is responsible for the differential MYC mediated transcriptional inhibition of MC-let-7a-1~let-7d and potentially other tumor suppressors. MYC and let-7 are key oncoprotein and tumor suppressor, respectively. Understanding the molecular mechanisms of their regulations will provide new insight and have important implications in the therapeutics of GBM as well as other cancers.
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Zifeng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Laboratory of Medical Genetics, Shenzhen Research Institute of Population and Family Planning, Shenzhen, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Lin
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Jiangsu Key Laboratory of Cancer Biotherapy, Xuzhou Medical College, Xuzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Gastrointestinal Surgery, Tumor Hospital, Xinjiang Medical University, Urumqi, Xinjiang Uyghur Autonomous Region, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ge
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.affiliation: School of Biomedical Science, and State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Hsiang-Fu
authors.initials: HF
authors.lastname: Kung
authors.affiliation: Brain Tumor Centre and Division of Neurosurgery, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Brain Tumor Centre and Division of Neurosurgery, Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
authors.forename: Wai Sang
authors.initials: WS
authors.lastname: Poon
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Shenzhen Key Laboratory of Translational Medicine of Tumor, School of Medicine, Shenzhen University, Shenzhen, China.
authors.forename: Marie Chia-Mi
authors.initials: MC
authors.lastname: Lin
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D024721:E-Box Elements / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D055815:Young Adult
chemical_list: C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; C487931:mirnlet7 microRNA, human
keywords: MC-let-7a-1~let-7d; MYC; glioblastoma; transcriptional regulation