OSR1 is a novel epigenetic silenced tumor suppressor regulating invasion and proliferation in renal cell carcinoma
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Yixiang Zhang1,*, Yeqing Yuan1,*, Pei Liang2,*, Xiaojing Guo3, Ying Ying4, Xing-Sheng Shu5, Michael Gao Jr2 and Yingduan Cheng6
1Department of Urology, The Second Affiliated Hospital of Jinan University, Shenzhen People’s Hospital, Shenzhen, Guangdong, China
2Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California USA
3Department of Pathology, The Second Affiliated Hospital of Jinan University, Shenzhen People’s Hospital, Shenzhen, Guangdong, China
4Department of Physiology, School of Basic Medical Sciences, Shenzhen University Health Sciences Center, Shenzhen, China
5Institute of Molecular Medicine, Health Science Center, Shenzhen University, Shenzhen, China
6Twigbiotechnology, Shenzhen, Guangdong, China
*These authors contribute equally to this work
Yingduan Cheng, email: [email protected]
Keywords: OSR1, methylation, invasion, proliferation, RCC
Received: November 14, 2016 Accepted: January 24, 2017 Published: February 22, 2017
Renal cell carcinoma (RCC) is one of the most malignant tumors in human. Here, we found that odd-skipped related transcription factor 1 (OSR1) was downregulated in 769-P and 786-O cells due to promoter CpG methylation. OSR1 expression could be restored by pharmacological demethylation treatment in silenced cell lines. Knockdown of OSR1 in two normal expressed cell lines- A498 and ACHN promoted cell invasion and cellular proliferation. RNA-Sequencing analysis showed that expression profile of genes involved in multiple cancer-related pathways was changed when OSR1 was downregulated. By quantitative real-time PCR, we confirmed that depletion of OSR1 repressed the expression of several tumor suppresor genes involved in p53 pathway, such as p53, p21, p27, p57 and RB in A498 and ACHN. Moreover, knockdown of OSR1 suppressed the transcriptional activity of p53. Of note, OSR1 depletion also led to increased expression of a few oncogenic genes. We further evaluated the clinical significance of OSR1 in primary human RCC specimens by immunohistochemical staining and found that OSR1 expression was downregulated in primary RCC and negatively correlated with histological grade. Thus, our data indicate that OSR1 is a novel tumor suppressor gene in RCC. Downregulation of OSR1 might represent a potentially prognostic marker and therapeutic target for RCC.
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