Oncotarget

Research Papers:

MELK is a novel therapeutic target in high-risk neuroblastoma

Shan Guan, Jiaxiong Lu, Yanling Zhao, Yang Yu, Hui Li, Zhenghu Chen, Zhongcheng Shi, Haoqian Liang, Mopei Wang, Kevin Guo, Xiangmei Chen, Wenjing Sun, Shayahati Bieerkehazhi, Xin Xu, Surong Sun, Saurabh Agarwal and Jianhua Yang _

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Oncotarget. 2018; 9:2591-2602. https://doi.org/10.18632/oncotarget.23515

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Abstract

Shan Guan1,2, Jiaxiong Lu2, Yanling Zhao2, Yang Yu2, Hui Li3,4, Zhenghu Chen2, Zhongcheng Shi2, Haoqian Liang2, Mopei Wang3,5, Kevin Guo2, Xiangmei Chen3,6, Wenjing Sun2,7, Shayahati Bieerkehazhi3, Xin Xu2, Surong Sun1, Saurabh Agarwal2 and Jianhua Yang2

1Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, China

2Texas Children’s Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA

3Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

4Department of Cardiothoracic Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China

5Department of Tumor Chemotherapy and Radiation Sickness, Peking University Third Hospital, Beijing 100083, China

6Peking University Health Science Center, Beijing 100083, China

7Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China

Correspondence to:

Jianhua Yang, email: [email protected]

Keywords: neuroblastoma; MYCN/MYC; MELK; chemotherapy; OTSSP167

Received: October 20, 2017     Accepted: December 08, 2017     Published: December 20, 2017

ABSTRACT

Maternal embryonic leucine zipper kinase (MELK) is known to modulate intracellular signaling and control cellular processes. However, the role of MELK in oncogenesis is not well defined. In this study, using two microarray datasets of neuroblastoma (NB) patients, we identified that MELK expression is significantly correlated to poor overall survival, unfavorable prognosis, and high-risk status. We found that MELK is a direct transcription target of MYCN and MYC in NB, and MYCN increases MELK expression via direct promoter binding. Interestingly, knockdown of MELK expression significantly reduced the phosphorylation of target protein Retinoblastoma (pRb) and inhibited NB cell growth. Furthermore, pharmacological inhibition of MELK activity by small-molecule inhibitor OTSSP167 significantly inhibited cell proliferation, anchorage-independent colony formation, blocked cell cycle progression, and induced apoptosis in different NB cell lines including a drug-resistant cell line. Additionally, OTSSP167 suppressed NB tumor growth in an orthotopic xenograft mouse model. Overall, our data suggest that MELK is a novel therapeutic target for NB and its inhibitor OTSSP167 is a promising drug for further clinical development.


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