Genomic characterization of genes encoding histone acetylation modulator proteins identifies therapeutic targets for cancer treatment

Zhongyi Hu,Kathleen T Montone,Junjie Jiang,Ie-Ming Shih,Nicki Loo,Yueying Wang,Yutian Pan,Junzhi Zhou,Lin Zhang,Janos L Tanyi,Xiaowen Hu,Xuepeng Wei,Yi Fan,Xiaomin Zhong,Jiao Yuan,Meixiao Long,Tianli Zhang,Youyou Zhang,Tian-Li Wang

doi:10.1038/s41467-019-08554-x

Abstract

A growing emphasis in anticancer drug discovery efforts has been on targeting histone acetylation modulators. Here we comprehensively analyze the genomic alterations of the genes encoding histone acetylation modulator proteins (HAMPs) in the Cancer Genome Atlas cohort and observe that HAMPs have a high frequency of focal copy number alterations and recurrent mutations, whereas transcript fusions of HAMPs are relatively rare genomic events in common adult cancers. Collectively, 86.3% (63/73) of HAMPs have recurrent alterations in at least 1 cancer type and 16 HAMPs, including 9 understudied HAMPs, are identified as putative therapeutic targets across multiple cancer types. For example, the recurrent focal amplification of BRD9 is observed in 9 cancer types and genetic depletion of BRD9 inhibits tumor growth. Our systematic genomic analysis of HAMPs across a large-scale cancer specimen cohort may facilitate the identification and prioritization of potential drug targets and selection of suitable patients for precision treatment.

Highlights

A growing emphasis in anticancer drug discovery efforts has been on targeting histone acetylation modulators
We found that most histone acetylation modulator proteins (HAMPs) were ubiquitously expressed across the 33 cancer types (Fig. 1a and Supplementary Data 3)
Similar expressional patterns were observed in corresponding normal adjacent tissues as well as established cancer cell lines (Supplementary Figure 1). These lineage-specific HAMPs were mainly detected in the cancer types derived from the tissues in which the corresponding HAMPs are normally expressed, they were ectopically expressed in a small fraction of other cancer types

Summary

Introduction

A growing emphasis in anticancer drug discovery efforts has been on targeting histone acetylation modulators. We comprehensively analyze the genomic alterations of the genes encoding histone acetylation modulator proteins (HAMPs) in the Cancer Genome Atlas cohort and observe that HAMPs have a high frequency of focal copy number alterations and recurrent mutations, whereas transcript fusions of HAMPs are relatively rare genomic events in common adult cancers. A BRD is a protein domain (~110 amino acids) that recognizes acetylated lysine residues in histone tails This recognition is a prerequisite for protein–histone association and chromatin remodeling. By integrating multi-omic profiles, we comprehensively characterized the genomic alterations of 73 HAMP genes (Supplementary Data 1)[1], including 18 HAT genes, 43 BRD-containing genes (including 6 HATs that contain BRDs), and 18 HDAC genes, across the whole TCGA data cohort (n > 10,000, including samples of 33 cancer types from 27 primary sites, Supplementary Data 2). Our integrated genomic study indicates that many uncharacterized HAMPs are putative cancer-causing genes with therapeutic potential in certain cancer types

Methods

Results

Conclusion