INPP5F translocates into cytoplasm and interacts with ASPH to promote tumor growth in hepatocellular carcinoma
Background Increasing evidence has suggested inositol polyphosphate 5-phosphatase family contributes to tumorigenesis and tumor progression. However, the role of INPP5F in hepatocellular carcinoma (HCC) and its underlying mechanisms is unclear. Methods The expression of INPP5F in HCC was analyzed in public databases and our clinical specimens. The biological functions of INPP5F were investigated in vitro and vivo. The molecular mechanism of INPP5F in regulating tumor growth were studied by
... ere studied by transcriptome-sequencing analysis, mass spectrometry analysis, immunoprecipitation assay and immunofluorescence assay. Results High expression of INPP5F was found in HCC tissues and was associated with poor prognosis in HCC patients. Overexpression of INPP5F promoted HCC cell proliferation, and vice versa. Knockdown of INPP5F suppressed tumor growth in vivo. Results from transcriptome-sequencing analysis showed INPP5F not only regulated a series of cell cycle related genes expression (c-MYC and cyclin E1), but also promoted many aerobic glycolysis related genes expression. Further study confirmed that INPP5F could enhance lactate production and glucose consumption in HCC cells. Mechanistically, INPP5F interacted with ASPH through which INPP5F activated Notch signaling and subsequently promoted the expression of c-MYC and cyclin E1. Interestingly, INPP5F was commonly nuclear-located in cells of adjacent tissues, while cytoplasmic-located was more common in HCC cells. LMB (nuclear export inhibitor) treatment restricted INPP5F in nucleus and was associated with inhibition of Notch signaling and cell proliferation. Furthermore, sequence of nuclear localization signals (NLSs) and nuclear export signals (NESs) in INPP5F aminoacidic sequence were identified. Alteration of the NLSs or NESs influenced the localization of INPP5F and the expression of its downstream molecules. Conclusion These findings indicate that INPP5F functions as an oncogene in HCC via a translocation mechanism and activating ASPH-mediated Notch signaling pathway. INPP5F may serve as a potential therapeutic target for HCC patients.