Histone Demethylase KDM4C Is Required for Ovarian Cancer Stem Cell Maintenance

Abstract

Ovarian cancer is a highly deadly disease, which is often diagnosed at a late stage with metastases. However, most ovarian cancers relapse after surgery combined with platinum-based chemotherapy. Cancer stem cells (CSCs) are stem-like cells that possess high tumorigenic capability and display higher resistant capability against current therapies. However, our knowledge of ovarian CSCs and their molecular mechanism remains sparse. In the current study, we found that KDM4C, a histone demethylase, was required for ovarian cancer stem cell (CSC) maintenance. Depletion of KDM4C significantly reduced the CSC population and sphere formation in vitro. Moreover, we found that KDM4C can regulate the expression of stem cell factor OCT-4 via binding to its promoter. These data indicate that KDM4C is relevant for ovarian CSC maintenance and underscore its importance as a potential therapeutic target.

Histone demethylase KDM4C is a functional dependency in JAK2-mutated neoplasms

“…Most recently, KDM4C has been described as a regulator of stemness [ 26 – 29 ], cancer cell resistance [ 30 , 31 ] and cancer progression [ 32 , 33 ] in various cancer models and KDM4C germline variants may increase multi-cancer vulnerability through dysregulation of target histone methylation [ 34 ]. In murine models of acute myeloid leukemia (AML) driven by MLL-rearrangements, genetic inactivation of all Kdm4 family members blunted leukemia development while inactivation of Kdm4c alone showed minor effects regarding proliferation of leukemic cells [ 21 ].…”

Transcriptomic and Drug Discovery Analyses Reveal Natural Compounds Targeting the KDM4 Subfamily as Promising Adjuvant Treatments in Cancer

“…In the present work we focus on the role of KDM4 subfamily members since they have been involved in cancer development for their ability to alter the chromatin’s state and influence gene expression ( García et al, 2016 ). KDM4A, B, C, and D’s expression is tightly regulated in non-neoplastic tissues but often deregulated in several neoplasias such as prostate, liver, bladder, colorectal, squamous cell carcinomas, acute myeloid leukemia, breast, lung and ovarian cancer ( Guerra-Calderas et al, 2015 , 2018 ; Lu et al, 2015 ; Lin et al, 2019 ; Chen et al, 2020 ; Wu et al, 2021 ). KDM4E’s expression has only been detected in testis, however, its physiological role remains unknown ( Hillringhaus et al, 2011 ).…”

KDM4C Promotes Proliferation and Migration of Multiple Myeloma Cells by Up-Regulating JAG1 Gene Expression

“…Therefore, it is essential to investigate the precise mechanism of multiple myeloma progression. KDM4C was demonstrated to be a vital regulator in cancers [6][7][8] , while little is known about its action on multiple myeloma. Thus, we studied the effect of KDM4C on multiple myeloma progression in this study.…”

“…Lysine Demethylase 4C (KDM4C), a histone demethylase, has been extensively described in cancers 4,5) . Accumulating evidence revealed that KDM4C exhibited deregulation in cancers, and it exerted a regulatory role in some cancers such as prostate cancer, ovarian cancer, and colon cancer [6][7][8] . For example, highly expressed KDM4C potentiated the proliferation ability of prostate cancer cells through activating AKT and c-Myc 6) .…”

“…For example, highly expressed KDM4C potentiated the proliferation ability of prostate cancer cells through activating AKT and c-Myc 6) . In ovarian cancer, KDM4C was overexpressed in the cancer stem cell population, and it was essential for the maintenance of ovarian cancer stem cell characteristics 7) . In colon cancer, abnormal expressed KDM4C modulated sphere formation ability in colon cancer cells through mediating the crosstalk between Wnt and Notch pathways 8) .…”