Abstract
BackgroundActivation of transcription enhancers, especially super-enhancers, is one of the critical epigenetic features of tumorigenesis. However, very few studies have systematically identified the enhancers specific in cancer tissues.MethodsHere, we studied the change of histone modifications in MMTV-PyVT breast cancer model, combining mass spectrometry-based proteomics and ChIP-seq-based epigenomics approaches. Some of the proteomic results were confirmed with western blotting and IHC staining. An inhibitor of H3K27ac was applied to study its effect on cancer development.ResultsH3K27ac and H4K8ac are elevated in cancer, which was confirmed in patient tissue chips. ChIP-seq revealed that H4K8ac is co-localized with H3K27ac on chromatin, especially on distal enhancers. Epigenomic studies further identified a subgroup of super-enhancers marked by H3K4me3 peaks in the intergenic regions. The H3K4me3-enriched regions enhancers are associated with higher level of H3K27ac and H4K8ac compared with the average level of conventional super-enhancers and are associated with higher transcription level of their adjacent genes. We identified 148 H3K4me3-enriched super-enhancers with higher gene expression in tumor, which may be critical for breast cancer. One inhibitor for p300 and H3K27ac, C646, repressed tumor formation probably through inhibiting Vegfa and other genes.ConclusionsTaken together, our work identifies novel regulators and provides important resource to the genome-wide enhancer studies in breast cancer and raises the possibility of cancer treatment through modulating enhancer activity.
Highlights
Activation of transcription enhancers, especially super-enhancers, is one of the critical epigenetic features of tumorigenesis
The proteomic studies of the normal and breast cancer tissues A mass spectrometry-based proteomic approach was utilized in this study to characterize histone post-translational modifications (PTMs) in the normal and breast cancer tissues of the MMTV-PyVT mice model
In the current study, our proteomics and western blotting results revealed that histone H3K27ac and H4K8ac are upregulated in the tumors of MMTV-PyVT mice, which was confirmed by IHC staining of human breast cancer tissues
Summary
Activation of transcription enhancers, especially super-enhancers, is one of the critical epigenetic features of tumorigenesis. Very few studies have systematically identified the enhancers specific in cancer tissues. The recent advances in epigenetics and genomics have revealed the critical roles of epigenetic factors in cancer. The dynamic regulation of histone acetylation and methylation becomes critical for chromatin stability, tumorigenesis, and metastasis [1,2,3]. Inhibitors for histone deacetylases (HDACs) have been approved to be used in clinical treatment, such as SAHA and VPA [4]. Inhibitors for histone acetylation readers have become another new family of promising drugs in cancer treatment [5]. Quite a few of histone methyltransferases and demethylases have been characterized as key molecules in cancer.
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