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Oncotarget. 2015 Nov 24;6(37):39891-907. doi: 10.18632/oncotarget.5359.

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

Author information

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.

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.

KEYWORDS:

INPP4B; SGK3; melanoma; miRNA-494; miRNA-599

PMID:
26573229
PMCID:
PMC4741868
DOI:
10.18632/oncotarget.5359
[Indexed for MEDLINE]
Free PMC Article

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