PCAF, ISX, and BRD4: a maleficent alliance serving lung cancer malignancy

Abstract

Tumor progression and malignancy are frequently associated with aberrant activation of epithelial-mesenchymal transition (EMT), which orchestrates dramatic changes in gene expression, involving genetic and epigenetic regulation. External stimuli generated by tumor-stroma interactions need to be adequately processed to specifically alter expression of key EMT transcription factors and associated genes. In this issue of EMBO Reports, Wang and colleagues demonstrate how epigenetic modifiers are utilized to induce EMT and metastasis [1]. Acetylation of intestine-specific homeobox (ISX) by p300/CBP-associated factor (PCAF) induces a cascade that results in Snail and Twist activation through histone modifications by a novel complex of PCAF, ISX, and bromodomain-containing protein 4 (BRD4). These findings open novel possibilities of therapeutic intervention to inhibit EMT and metastasis in lung cancer.

Figure 1. The PCAF‐ISX‐BRD4 axis induces EMT by driving Snail and Twist expression in lung cancer

(A) Model of regulation of key EMT genes by ISX, BRD4, and PCAF. PCAF promotes acetylation (Ac) of ISX and BRD4 in the cytoplasm, which leads to the formation of a ternary complex that translocates to the nucleus. Via histone H3 acetylation on specific genes such as Snail and Twist, this complex modifies chromatin, and allows histone displacement and recruitment of the transcription machinery, including p300 and RNA polymerase II (Pol II), to activate gene expression for EMT induction. (B) Potential sites of therapeutic intervention to interfere with PCAF‐ISX‐BRD4 function. The small‐molecule inhibitor garcinol prevents acetylation by PCAF; JQ1 disrupts BRD4 binding to acetylated H3 in a global manner. Generation of inhibitors or small peptides (inh1, inh2, and inh3) that block binding of ISX‐BRD4, ISX‐PCAF, and PCAF‐BRD4, respectively, might specifically inhibit EMT and metastasis.