INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas

// Meng Na Chi 1, * , Su Tang Guo 2, 3, * , James S. Wilmott 4 , Xiang Yun Guo 3 , Xu Guang Yan 1 , Chun Yan Wang 2, 3 , Xiao Ying Liu 2 , Lei Jin 1 , Hsin-Yi Tseng 2 , Tao Liu 5 , Amanda Croft 2 , Hubert Hondermarck 2 , Richard A. Scolyer 4 , Chen Chen Jiang 1 , Xu Dong Zhang 1, 2 1 School of Medicine and Public Health, The University of Newcastle, NSW 2308, Australia 2 School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW 2308, Australia 3 Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi 030013, China 4 Discipline of Pathology, The University of Sydney, and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2006, Australia 5 Children'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 Correspondence to: 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 ABSTRACT 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.