Research Papers:

Loss of MYC and E-box3 binding contributes to defective MYC-mediated transcriptional suppression of human MC-let-7a-1~let-7d in glioblastoma

Zifeng Wang, Sheng Lin, Ji Zhang, Zhenhua Xu, Yu Xiang, Hong Yao, Lei Ge, Dan Xie, Hsiang-fu Kung, Gang Lu, Wai Sang Poon, Quentin Liu and Marie Chia-mi Lin _

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Oncotarget. 2016; 7:56266-56278. https://doi.org/10.18632/oncotarget.10517

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Zifeng Wang1, Sheng Lin4, Ji Zhang1, Zhenhua Xu5, Yu Xiang1, Hong Yao6, Lei Ge8, Dan Xie1, Hsiang-fu Kung7, Gang Lu3, Wai Sang Poon3, Quentin Liu1, Marie Chia-mi Lin2

1Sun 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

2Shenzhen Key Laboratory of Translational Medicine of Tumor, School of Medicine, Shenzhen University, Shenzhen, China

3Brain 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

4Laboratory of Medical Genetics, Shenzhen Research Institute of Population and Family Planning, Shenzhen, China

5Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA

6Jiangsu Eng. Laboratory of Cancer Biotherapy, Xuzhou Medical College, Xuzhou, China

7School of Biomedical Science, and State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Shatin, Hong Kong

8Department of Gastrointestinal Surgery, Tumor Hospital, Xinjiang Medical University, Urumqi, Xinjiang Uyghur Autonomous Region, China

Correspondence to:

Marie Chia-mi Lin, email: mcmlin@163.com

Quentin Liu, email: liuq9@mail.sysu.edu.cn

Keywords: MC-let-7a-1~let-7d, MYC, glioblastoma, transcriptional regulation

Received: October 16, 2015     Accepted: May 20, 2016     Published: July 09, 2016


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.

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