JMJD family proteins in cancer and inflammation

Abstract

The occurrence of cancer entails a series of genetic mutations that favor uncontrollable tumor growth. It is believed that various factors collectively contribute to cancer, and there is no one single explanation for tumorigenesis. Epigenetic changes such as the dysregulation of enzymes modifying DNA or histones are actively involved in oncogenesis and inflammatory response. The methylation of lysine residues on histone proteins represents a class of post-translational modifications. The human Jumonji C domain-containing (JMJD) protein family consists of more than 30 members. The JMJD proteins have long been identified with histone lysine demethylases (KDM) and histone arginine demethylases activities and thus could function as epigenetic modulators in physiological processes and diseases. Importantly, growing evidence has demonstrated the aberrant expression of JMJD proteins in cancer and inflammatory diseases, which might serve as an underlying mechanism for the initiation and progression of such diseases. Here, we discuss the role of key JMJD proteins in cancer and inflammation, including the intensively studied histone lysine demethylases, as well as the understudied group of JMJD members. In particular, we focused on epigenetic changes induced by each JMJD member and summarized recent research progress evaluating their therapeutic potential for the treatment of cancer and inflammatory diseases.

Targeting epigenetic regulators to overcome drug resistance in cancers

“…204,205 It has been reported that JMJD1A can upregulate DCLK1 and CDK6 in a demethylationdependent manner and maintain the occurrence and development of pancreatic cancer. 206,207 The JMJD2 (KDM4) family: The JMJD2 (KDM4) family consists of six proteins (JMJD2A-F), 208,209 all the proteins have the ability to demethylate H3K9me2/me3 and H3K36me2/me3, which are conductive to breast, colorectal, prostate and other cancers formation (Fig. 5).…”

Chemical Inhibitors Targeting the Histone Lysine Demethylase Families with Potential for Drug Discovery

“…Several reports indicate that KDM4 family members are over-expressed in various cancers: KDM4A, KDM4B, and KDM4C are over-expressed in prostate cancer [ 74 ]; amplification of KDM4B is shown in medulloblastoma [ 77 ]; and KDM4C is required for the growth of breast carcinoma [ 78 ] and diffuse large B cell lymphoma [ 79 ]. These family members are involved in diverse biological pathways linked to cancer such as Akt-mTOR signaling for KDM4A, Wnt signaling for KDM4B, targeting pluripotency factors for KDM4C, and hypoxia-inducible factor 1 signaling for KDM4D [ 23 ]. Although the cellular functions of KDM4 demethylases are yet to be fully characterized, studies show that the demethylation of, for example, H3K9me3 at promoter regions, correlates with the activation of associated genes [ 80 ].…”

“…Dysregulation of several KDMs has also been implicated in diseases including cancer and inflammation [ 15 , 20 ]. The histone methylation states (e.g., Kme0 to Kme3) can be linked to unique biological activities [ 21 ] and the potential signaling mechanisms and biological pathways involved in diseases for each KMT family member have been summarized in recent reviews [ 20 , 22 , 23 ]. Therefore, this review focused on the lysine demethylase family.…”

Small Molecules as Anti‐inflammatory Agents: Molecular Mechanisms and Heterocycles as Inhibitors of Signaling Pathways

“…[3] Unlike acute inflammation, chronic inflammation could cause cancer due to uncontrolled cell proliferation and reduced DNA repair. [4][5][6] Inflammation plays a vital role in different pathological diseases; on the other side, cancer development involves a multi-step process. A better understanding of inflammatory pathways and the molecular mechanisms that lead to cancer contributes to improved prevention and treatment of inflammatory disease.…”

“…Apart from this, inflammation is also induced by chemicals and microbial agents [3] . Unlike acute inflammation, chronic inflammation could cause cancer due to uncontrolled cell proliferation and reduced DNA repair [4–6] . Inflammation plays a vital role in different pathological diseases; on the other side, cancer development involves a multi‐step process.…”