- Title
- INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas
- Creator
- Chi, Meng Na; Guo, Su Tang; Croft, Amanda; Hondermarck, Hubert; Scolyer, Richard A.; Jiang, Chen Chen; Zhang, Xu Dong; Wilmott, James S.; Guo, Xiang Yun; Yan, Xu Guang; Wang, Chun Yan; Liu, Xiao Ying; Jin, Lei; Tseng, Hsin-Yi; Liu, Tao
- Relation
- NHMRC.1026458
- Relation
- Oncotarget Vol. 6, Issue 37, p. 39891-39907
- Publisher Link
- http://dx.doi.org/10.18632/oncotarget.5359
- Publisher
- Impact Journals
- Resource Type
- journal article
- Date
- 2015
- Description
- 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.
- Subject
- INPP4B; SGK3; melanoma; miRNA-494; miRNA-599
- Identifier
- http://hdl.handle.net/1959.13/1314949
- Identifier
- uon:22865
- Identifier
- ISSN:1949-2553
- Language
- eng
- Full Text
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