Cancer directly affects at least one-third of the human population. Despite this extensive research prevalence, the genetic determinants of cancer risk remain largely unknown. Metastasis, a complex, multistep morphogenetic process, refers to the dissemination from a primary tumor mass to distal tissues, with epithelial–mesenchymal transition (EMT) believed to be the initial and vital step. Despite several signaling (e.g., PI3K, snail, HIF1α, and SIP1) and transcriptional (TWIST1/2, SNAIL1/2, ZEB1/2, and FOXC2) factors having been identified as major regulators of EMT, a detailed regulatory mechanism for oncogene-induced EMT has yet to be established. Epigenetic regulation is an important process during cancer progression, however, the underlying mechanisms, particularly those involving protein acetylation, remain to be fully understood. Recently, Prof. Hsu (GIM, KMU) found intestine-specific homeobox (ISX), a newly identified pair-family homeobox transcription factor, is a pro-inflammatory cytokine (IL-6) induced homeobox gene and high expression in hepatoma cells and HCC patients. Through directly regulates downstream cell cycle regulators (cyclin D1 and E2F1), ISX shows high correlation to patient survival time, tumor size, tumor number and progression stage, and accelerated cell proliferation and tumorigenic activity in hepatoma cells which highlights ISX is an important regulator in hepatoma progression with significant potential as a prognostic and therapeutic target in HCC. In addition, the exposure of environmental pollutants will also trigger and exacerbate the occurrence of liver cancer by inducing the ISX and relevant epigenetic genes expression via the function of its upstream regulatory gene-AHR. At the same time, the expression of ISX in HCC cells can also inhibit the host's own immune system through the regulation of immune checkpoint and tryptophan metabolism-related genes to promote the further growth and metastasis of hepatoma cells. Here, we show that P300/CBP-associated factor (PCAF)-dependent acetylation of intestine-specific homeobox (ISX) regulates epithelial-mesenchymal transition (EMT) and promotes cancer metastasis. Mechanistically, PCAF acetylation of ISX at lysine 69 promotes the interaction with acetylated bromodomain-containing protein 4 (BRD4) at lysine 332 in tumor cells, and the translocation of the resulting complex into the nucleus. There, it binds to promoters of EMT genes, where acetylation of histone 3 at lysines 9, 14, and 18 initiates chromatin remodeling and subsequent transcriptional activation. Ectopic ISX expression enhances EMT marker expression, including TWIST1, Snail1, and VEGF, induces cancer metastasis, but suppresses E-cadherin expression. In lung cancer, ectopic expression of PCAF–ISX–BRD4 axis components correlates with clinical metastatic features and poor prognosis. These results suggest that the PCAF–ISX–BRD4 axis mediates EMT signaling and regulates tumor initiation and metastasis.

Full paper linkage: https://pubmed.ncbi.nlm.nih.gov/31908141/

Figure legend: Illustration of experimental data and structure modeling, it is demonstrated that Tyr390 and Asn433 residues on the BD2 domain of BRD4 are critical residues needed for BRD4 to recognize and bind with the acetylated Lys69 of ISX to facilitate the formation of the ISX–BRD4 complex.

Main researcher Intro.

Professor Hsu Shih-Hsien, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Author Email

Professor Hsu: jackhsu@kmu.edu.tw, TEL:07-3121101#2136

Paper cited from:

EMBO Rep. 2020 Feb 5;21(2):e48795.

Research Paper available online on website:

https://pubmed.ncbi.nlm.nih.gov/31908141/