Histone lysine demethylase PHF8 (PHF8) (PHF8)

Histone lysine demethylase PHF8 (PHF8), also known as KDM7B, is a JmjC domain-containing enzyme that plays a pivotal role in epigenetic regulation by demethylating mono- and di-methylated histone H3 lysine 9 (H3K9me1/2), H3 lysine 27 (H3K27me2), and H4 lysine 20 (H4K20me1) [1, 3]. It is characterized by its ability to link histone demethylation with the recognition of trimethylated H3K4 via its PHD finger, thereby coordinating gene activation [1, 4]. PHF8 is essential for normal brain development and ribosomal RNA transcription, and its genetic dysfunction is linked to X-linked intellectual disability (Siderius type) and craniofacial defects [3, 5]. In the context of oncology, PHF8 is frequently overexpressed and functions as an oncoprotein that promotes cell cycle progression, epithelial-mesenchymal transition, and metastasis in various malignancies, including prostate, breast, and lung cancers [4, 7]. Therapeutic strategies targeting PHF8 primarily involve small-molecule inhibitors that compete with the alpha-ketoglutarate cofactor or RNA-interference approaches to reduce PHF8 mRNA levels [6, 8]. Experimental inhibitors such as daminozide and various JmjC-family antagonists are being studied for their ability to restore repressive histone marks and suppress tumor growth [5, 6]. However, achieving high selectivity over other JmjC family members remains a significant challenge in drug development [8]. Potential safety concerns include developmental toxicity and global epigenetic dysregulation due to the widespread role of PHF8 in gene expression [3, 5].

Other names

KDM7BPlant homeodomain finger protein 8JmjC domain-containing histone demethylation protein 1FJHDM1FMRX71ZNF422

Competitive inhibition of the alpha-ketoglutarate binding site within the JmjC catalytic domain to prevent oxidative demethylation of histone substrates.