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

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.

• Authors: Meng Na Chi, Su Tang Guo, James S Wilmott, Xiang Yun Guo, Xu Guang Yan, Chun Yan Wang, Xiao Ying Liu, Lei Jin, Hsin-Yi Tseng, Tao Liu, Amanda Croft, Hubert Hondermarck, Richard A Scolyer, Chen Chen Jiang, Xu Dong Zhang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 37 Pg. 39891-907 (Nov 24 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26573229 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MIRN494 microRNA, human
• MIRN599 microRNA, human
• MicroRNAs
• Protein Serine-Threonine Kinases
• SGK3 protein, human
• Phosphoric Monoester Hydrolases
• phosphatidylinositol-3,4-bisphosphate 4-phosphatase

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Immunoblotting
• Immunohistochemistry
• Male
• Melanoma (genetics, metabolism, pathology)
• Mice, Nude
• MicroRNAs (genetics)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoric Monoester Hydrolases (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (genetics)
• Transplantation, Heterologous
• Tumor Burden (genetics)
• Up-Regulation