SH2D4A mediated the regulation of OTUD4 on malignant behavior of ovarian cancer cells: the function of SH2D4A-HDGF axis

Ovarian cancer is recognized as the most lethal gynecological malignancy. Based on our previous work and proteomics, it was established that ovarian tumor family deubiquitinase 4 (OTUD4) restrained the malignant behavior of ovarian cancer and bound to SH2 domain containing 4 A (SH2D4A). Meanwhile, SH2D4A was lowly expressed in clinical ovarian cancer tissues. However, the function of SH2D4A in ovarian cancer remains unknown. The high-grade serous ovarian cancer cells OVCAR8 and CAOV3 were used as in vitro models and OVCAR8 tumor-bearing mouse was used as in-vivo model to investigate the function and mechanism of SH2D4A in ovarian cancer. Our results demonstrated that overexpression of SH2D4A suppressed cell proliferation and clone formation with the evidence of flow cytometry and clone formation assay, knockdown of SH2D4A showed an opposite trend. At the same time, SH2D4A overexpression enhances cisplatin (DDP) chemosensitivity in ovarian cancer cells and tumor-bearing mice. For specific mechanism, SH2D4A knockdown abolished the therapeutic effect of OTUD4 overexpression on malignant phenotype which indicated that the effect of OTUD4 on ovarian cancer was mediated by SH2D4A. Subsequently, Hepatoma-derived growth factor (HDGF) was screened out by intersection between SH2D4A interacting proteins and cisplatin and ovarian cancer related factors. With the evidence of immunofluorescent and western blot, HDGF showed a low expression in nucleus when SH2D4A was overexpressed, and exogenous HDGF abolished the effects of SH2D4A on cell proliferation and apoptosis. In total, SH2D4A is regulated by OTUD4 and restricted the malignant phenotype of ovarian cancer cells by binding to HDGF and inhibiting its nuclear translocation. Therefore, as one of the downstream targets of OTUD4, the SH2D4A/HDGF axis may represent a new pathway for regulating the progression of ovarian cancer.