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.
Highlights
Aberrant activation of survival-signalling pathways causes uncontrolled cell proliferation and resistance to apoptosis, and plays an important role in cancer development, progression, and resistance to treatment [1, 2]
We provide evidence that INPP4B is upregulated in a subset of melanomas and plays a role in melanoma cell proliferation independently of Akt through activating phosphatidylinositol 3-kinase (PI3K)/serum- and glucocorticoid-regulated kinase 3 (SGK3) signalling
We examined the expression of INPP4B in relation to melanoma development and progression by immunohistochemistry (IHC) in tissue microarrays (TMAs) constructed from 100 formalin-fixed paraffinembedded (FFPE) melanocytic tumours using an antibody against INPP4B that had been used for similar studies in other types of tissues (Supplementary Table 1) [26, 32]
Summary
Aberrant activation of survival-signalling pathways causes uncontrolled cell proliferation and resistance to apoptosis, and plays an important role in cancer development, progression, and resistance to treatment [1, 2]. PI3K signalling is initiated with the engagement of extracellular growth factors to receptor tyrosine kinases (RTKs). This results in recruitment of PI3K to plasma membrane-anchored receptors where it is activated, leading to increases in the production of phosphatidylinositol(3,4) bisphosphate (PI(3,4)P2) and phosphatidylinositol(3,4,5) trisphosphate (PI(3,4,5)P3), which in turn bind to and activate multiple downstream effectors [11,12,13]. Activated Akt phosphorylates a large array of substrates to promote cell survival and proliferation [16, 17]
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