KDM4 Involvement in Breast Cancer and Possible Therapeutic Approaches

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.

Modulation of the activity of histone lysine methyltransferases and demethylases by curcumin analog in leukaemia cells

“…In support of that, LSD1 is overexpressed in haematologic malignancies and its inhibition induced differentiation of AML cells through the downregulation of the chromatin protein GSE1 33 . Similarly, the oncogenic role of JMJD2 in AML, hepatocellular, breast cancer and colorectal cancer was also reported 34,35 . Nonetheless, the demethylase activity of JMJD2 was shown to be essential for the long‐term maintenance of normal haematopoiesis 36 .…”

“… 33 Similarly, the oncogenic role of JMJD2 in AML, hepatocellular, breast cancer and colorectal cancer was also reported. 34 , 35 Nonetheless, the demethylase activity of JMJD2 was shown to be essential for the long‐term maintenance of normal haematopoiesis. 36 On the contrary, the impact of JARID1 activation on the antitumor effect of DMC and curcumin is not clear because of the oncogenic and tumour suppressive functions of JARID1 proteins, which are contingent on the protein isoform (JARID1A, JARID1B, JARID1C, JARID1D) and cell context.…”

SUMO Modification of Histone Demethylase KDM4A in Kaposi’s Sarcoma-Associated Herpesvirus-Induced Primary Effusion Lymphoma

“…Since SUMOylation is required for chromatin binding and consequently demethylase activity of KDM4A, rescuing overexpression of KDM4A-K471R mimics the knockdown phenotype ( 25 ). In addition to the viral effect, KDM4A has also been recognized as an oncogene that is highly expressed in various human cancers ( 40 , 41 ) and inhibits apoptosis ( 42 – 44 ). Therefore, we hypothesize that induction of KSHV reactivation in KDM4A knockdown BCBL-1 cells or cells expressing a SUMO-deficient mutant of KDM4A may lead to incomplete viral lytic replication and cell death.…”

Association of H3K9me3 with breast cancer prognosis by estrogen receptor status

“…Many cellular experiments revealed that a decreased level of H3K9me3 was associated with the overexpression of oncogenes; interestingly, some of these oncogenes were regulated by ER [ 19 , 25 , 27 , 29 ]. These findings supported our result that the low level of H3K9me3 was associated with a poor prognosis and this association was significant only in ER-positive (particularly ER-high positive) patients but not in ER-negative patients.…”