title: 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.affiliation: School of Medicine and Public Health, The University of Newcastle, NSW 2308, Australia.
authors.forename: Meng Na
authors.initials: MN
authors.lastname: Chi
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW 2308, Australia.|Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi 030013, China.
authors.forename: Su Tang
authors.initials: ST
authors.lastname: Guo
authors.affiliation: Discipline of Pathology, The University of Sydney, and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2006, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.affiliation: Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi 030013, China.
authors.forename: Xiang Yun
authors.initials: XY
authors.lastname: Guo
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, NSW 2308, Australia.
authors.forename: Xu Guang
authors.initials: XG
authors.lastname: Yan
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW 2308, Australia.|Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi 030013, China.
authors.forename: Chun Yan
authors.initials: CY
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW 2308, Australia.
authors.forename: Xiao Ying
authors.initials: XY
authors.lastname: Liu
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, NSW 2308, Australia.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW 2308, Australia.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Tseng
authors.affiliation: Children's Cancer Institute Australia for Medical Research, The University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW 2308, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Croft
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW 2308, Australia.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hondermarck
authors.affiliation: Discipline of Pathology, The University of Sydney, and Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2006, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, NSW 2308, Australia.
authors.forename: Chen Chen
authors.initials: CC
authors.lastname: Jiang
authors.affiliation: School of Medicine and Public Health, The University of Newcastle, NSW 2308, Australia.|School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW 2308, Australia.
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D015854:Up-Regulation; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; C547168:MIRN494 microRNA, human; C000608803:MIRN599 microRNA, human; C403243:SGK3 protein, human; D000099184:Serum-Glucocorticoid Regulated Kinases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase
keywords: INPP4B; SGK3; melanoma; miRNA-494; miRNA-599