Abstract
A wide range of the epigenetic effectors that regulate chromatin modification, gene expression, genomic stability, and DNA repair contain structurally conserved domains called plant homeodomain (PHD) fingers. Alternations of several PHD finger-containing proteins (PHFs) due to genomic amplification, mutations, deletions, and translocations have been linked directly to various types of cancer. However, little is known about the genomic landscape and the clinical significance of PHFs in breast cancer. Hence, we performed a large-scale genomic and transcriptomic analysis of 98 PHF genes in breast cancer using TCGA and METABRIC datasets and correlated the recurrent alterations with clinicopathological features and survival of patients. Different subtypes of breast cancer had different patterns of copy number and expression for each PHF. We identified a subset of PHF genes that was recurrently altered with high prevalence, including PYGO2 (pygopus family PHD finger 2), ZMYND8 (zinc finger, MYND-type containing 8), ASXL1 (additional sex combs like 1) and CHD3 (chromodomain helicase DNA binding protein 3). Copy number increase and overexpression of ZMYND8 were more prevalent in Luminal B subtypes and were significantly associated with shorter survival of breast cancer patients. ZMYND8 was also involved in a positive feedback circuit of the estrogen receptor (ER) pathway, and the expression of ZMYND8 was repressed by the bromodomain and extra terminal (BET) inhibitor in breast cancer. Our findings suggest a promising avenue for future research—to focus on a subset of PHFs to better understand the molecular mechanisms and to identify therapeutic targets in breast cancer.
Highlights
Histone modifications, such as methylation and acetylation, play critical roles in chromatin function, transcriptional regulation, genomic stability, and DNA repair [1, 2]
We found that 17 PHF genes, including PYGO2, KDM5B, PHF20L1, and ZMYND8, had a higher frequency (>10%) of gain/amplification, and 9 PHF genes, including CHD3 and PHF23, had a higher frequency of deletion in the METABRIC breast cancer samples (Supplementary Table 6), the frequency of gain/amplification identified in the METABRIC dataset is lower than that of The Cancer Genome Atlas (TCGA) dataset, possibly due to the different copy number alteration (CNA) analysis platforms and calling algorithms
In our analysis of the genetic alterations of PHFs in breast cancer, we found that ZMYND8 had a higher frequency of amplification and overexpression in Luminal B breast cancer, and its overexpression was associated with shorter survival in patients in both TCGA and METABRIC datasets
Summary
Histone modifications, such as methylation and acetylation, play critical roles in chromatin function, transcriptional regulation, genomic stability, and DNA repair [1, 2] These epigenetic modifications are mediated by sets of enzymatic complexes that have complementary but opposing functions, namely the “writers,” which catalyze methylation and acetylation in a site-specific manner, and the “erasers,” which remove the modification marks [1, 2]. Such modification marks are interpreted by “reader” proteins that recognize and are recruited to the modified histone [3, 4]. When PHFs malfunction, they are implicated in a broad range of human diseases, including cancer
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