KDM6A Exhibits Antitumor Activities Toward Ovarian Cancer by Epigenetically Activating Transcription of ISG-15

Ovarian cancer (OC) is a leading cause of cancer-related mortality among females worldwide. Lysine demethylase 6A (KDM6A) plays a crucial role in multiple physiological and pathological processes. However, its role in ovarian carcinogenesis remains unclear. The expression of KDM6A and survival analysis in OC were assessed utilizing GEPIA and Kaplan-Meier plotter databases. The expression of KDM6A was evaluated immunohistochemically in tissue samples from 55 OC patients. The CCK-8, Colony formation, and Transwell assays were employed to assess the ability of OC cells in proliferation, migration, and invasion. Lung metastasis and subcutaneous tumor models were used to evaluate the function of KDM6A in vivo. RNA sequencing, Western blot, and quantitative polymerase chain reaction were conducted to investigate the molecular functions of KDM6A. A chromatin immunoprecipitation assay was employed to determine the effects of KDM6A on the promoters of ubiquitin-like protein interferon-stimulated gene 15 (ISG-15). KDM6A expression was downregulated in OC and associated with poor progression-free survival and overall survival. KDM6A inhibits OC cell proliferation, migration, and invasion in vitro. Xenograft models have also confirmed the antitumor role of KDM6A in OC growth and metastasis. The mechanistic study demonstrated that KDM6A exerted an antitumor effect in a histone-demethylase-dependent manner by epigenetically activating ISG-15 transcription. KDM6A, a functional tumor suppressor, is frequently downregulated in OC. The KDM6A-ISG-15 axis is critical in restraining OC malignancy and may serve as a potential molecular target for novel therapies.