Abstract
Breast cancer (BC) is the second leading cause of cancer death in women, although recent scientific and technological achievements have led to significant improvements in progression-free disease and overall survival of patients. Genetic mutations and epigenetic modifications play a critical role in deregulating gene expression, leading to uncontrolled cell proliferation and cancer progression. Aberrant histone modifications are one of the most frequent epigenetic mechanisms occurring in cancer. In particular, methylation and demethylation of specific lysine residues alter gene accessibility via histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). The KDM family includes more than 30 members, grouped into six subfamilies and two classes based on their sequency homology and catalytic mechanisms, respectively. Specifically, the KDM4 gene family comprises six members, KDM4A-F, which are associated with oncogene activation, tumor suppressor silencing, alteration of hormone receptor downstream signaling, and chromosomal instability. Blocking the activity of KDM4 enzymes renders them “druggable” targets with therapeutic effects. Several KDM4 inhibitors have already been identified as anticancer drugs in vitro in BC cells. However, no KDM4 inhibitors have as yet entered clinical trials due to a number of issues, including structural similarities between KDM4 members and conservation of the active domain, which makes the discovery of selective inhibitors challenging. Here, we summarize our current knowledge of the molecular functions of KDM4 members in BC, describe currently available KDM4 inhibitors, and discuss their potential use in BC therapy.
Highlights
Breast cancer (BC) is the second leading cause of cancer death in women worldwide with a 0.5% increase in incidence rate per year
Findings from this study suggest that the inhibitor targets KDM4B in late S-phase due to activation of PLK1 transcription via B-MYB, justifying the development of this KDM4B inhibitor for androgen receptor (AR)+ prostate cancer and opening up the possibility for new treatments in the AR+ subgroup of BC [93]
Some epigenetic mechanisms and functions of KDM4 proteins associated with carcinogenesis remain unclear, a growing body of evidence indicates that KDM4 inhibitors are good candidates as anticancer drugs for various malignancies, including BC
Summary
Breast cancer (BC) is the second leading cause of cancer death in women worldwide with a 0.5% increase in incidence rate per year. KDM4D promotes cancer progression by directly interacting with hypoxia-inducible factor (HIF) 1b gene and activating its expression via H3K9me3 demethylation of the vascular endothelial growth factor A promoter region [57]. KDM4s are responsible in controlling development and proliferation of mammary gland [61], and their altered expression (mainly gene amplification) can promote cell transformation, migration, and invasion, all hallmarks of tumorigenesis in BC [47] (Figure 3).
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