KDM4

A Novel Epigenetic Target for Cancer Therapy

Genetic mutations are not the only way to alter gene expression. Epigenetic processes can also alter gene activity without changing the DNA sequence. It controls how the DNA is read by cells and determines which genes are switched on or off. Epigenetic modifications include a variety of mechanisms that “mark” DNA or histones such as methylation, acetylation, or phosphorylation that result in a remodeling of chromatin that ultimately lead to changes in gene expression.

 

An important mode of epigenetic regulation is facilitated through chromatin remodeling that results from modifications on histone proteins. The KDM4 proteins (KDM4A, B, C, and D) are a family of histone demethylases that catalyze the removal of methyl marks on histone H3, leading to transitions between transcriptionally silent and transcriptionally active chromatin states.

Overexpression of KDM4 can result in the disruption of crucial pathways leading to cancer, such as inhibition of apoptosis, uncontrolled gene expression, cell proliferation, genomic instability and metastasis.  In addition, KDM4 plays an important role in the self-renewal of cancer stem cells.

 

KDM4 overexpression has been associated with many cancer types, including breast, colorectal, esophageal, prostate, and lymphomas. Thus, KDM4 has emerged as an epigenetic therapeutic target for Tachyon’s novel platform of anticancer drugs.
TACH101 is a first-in-class small-molecule inhibitor of KDM4 that is currently being developed for the treatment of advanced or metastatic cancers.