Abstract 4718: Inositol polyphosphate 4-phosphatase II activates PI3K/SGK3 signaling to promote proliferation of human melanoma cells

Abstract Inositol polyphosphate 4-phosphatase type II (INPP4B) inhibits phosphatidylinositol 3-kinase (PI3K)/Akt signaling and is emerging as a tumor suppressor in a variety of tissues. Here we report that, conversely, it functions as an oncogenic regulator in human melanoma through activating PI3K/SGK3 signaling. While it was upregulated in a subset of melanomas, knockdown of INPP4B inhibited melanoma cell proliferation in vitro, and retarded melanoma growth in a xenograft model. In contrast, overexpression of INPP4B resulted in increased proliferation and anchorage-independent growth of melanocytes. Strikingly, INPP4B did not impinge on activation of Akt in melanocytic cells. Instead, it promoted PI3K/SGK3 signaling, in that INPP4B knockdown inhibited, whereas overexpression of INPP4B enhanced, activation of SGK3. Indeed, the effect of INPP4B on melanocytic cell proliferation was due to enhanced activation of SGK3, as co-introduction of an active form of SGK3 rescued melanocytes and melanoma cells from inhibition of proliferation triggered by INPP4B knockdown, and knockdown of SGK3 abolished enhancement in cell proliferation resulting from INPP4B overexpression. Upregulation of INPP4B appeared largely due to downregulation of microRNA-494 (miR-494) and/or miR-599 as a result of gene copy number reduction in melanoma cells. Collectively, these results reveal that INPP4B upregulation mediated by loss of miR-494 and/or miR-599 promotes melanoma cell proliferation through activation of PI3K/SGK3 signaling, and suggest that the role of INPP4B in the pathogenesis of cancers of different origins needs to be defined discretely. Citation Format: Chen Chen Jiang, 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, Amanda Croft, Hubert Hondermarck, Tao Liu, Richard A. Scolyer, Xu Dong Zhang. Inositol polyphosphate 4-phosphatase II activates PI3K/SGK3 signaling to promote proliferation of human melanoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4718. doi:10.1158/1538-7445.AM2015-4718