INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas
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Meng Na Chi1,*, Su Tang Guo2,3,*, James S. Wilmott4, Xiang Yun Guo3, Xu Guang Yan1, Chun Yan Wang2,3, Xiao Ying Liu2, Lei Jin1, Hsin-Yi Tseng2, Tao Liu5, Amanda Croft2, Hubert Hondermarck2, Richard A. Scolyer4, Chen Chen Jiang1, Xu Dong Zhang1,2
1School of Medicine and Public Health, The University of Newcastle, NSW 2308, Australia
2School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW 2308, Australia
3Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi 030013, China
4Discipline of Pathology, The University of Sydney, and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2006, Australia
5Children's Cancer Institute Australia for Medical Research, The University of New South Wales, Sydney, NSW 2052, Australia
*These authors have contributed equally to this work
Xu Dong Zhang, e-mail: Xu.Zhang@newcastle.edu.au
Chen Chen Jiang, e-mail: Chenchen.Jiang@newcastle.edu.au
Keywords: INPP4B, SGK3, melanoma, miRNA-494, miRNA-599
Received: May 06, 2015 Accepted: October 27, 2015 Published: November 09, 2015
Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates PI3K/Akt signalling and has a tumour suppressive role in some types of cancers. However, we have found that it is upregulated in a subset of melanomas. Here we report that INPP4B can function as an oncogenic driver through activation of serum- and glucocorticoid-regulated kinase 3 (SGK3) in melanoma. While INPP4B knockdown inhibited melanoma cell proliferation and retarded melanoma xenograft growth, overexpression of INPP4B enhanced melanoma cell and melanocyte proliferation and triggered anchorage-independent growth of melanocytes. Noticeably, INPP4B-mediated melanoma cell proliferation was not related to activation of Akt, but was mediated by SGK3. Upregulation of INPP4B in melanoma cells was associated with loss of miRNA (miR)-494 and/or miR-599 due to gene copy number reduction. Indeed, overexpression of miR-494 or miR-599 downregulated INPP4B, reduced SGK3 activation, and inhibited melanoma cell proliferation, whereas introduction of anti-miR-494 or anti-miR-599 upregulated INPP4B, enhanced SGK3 activation, and promoted melanoma cell proliferation. Collectively, these results identify upregulation of INPP4B as an oncogenic mechanism through activation of SGK3 in a subset of melanomas, with implications for targeting INPP4B and restoring miR-494 and miR-599 as novel approaches in the treatment of melanomas with high INPP4B expression.
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