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

• Published in: Nature communications Vol. 10; no. 1; pp. 733 - 17
• Main Authors: Hu, Zhongyi, Zhou, Junzhi, Jiang, Junjie, Yuan, Jiao, Zhang, Youyou, Wei, Xuepeng, Loo, Nicki, Wang, Yueying, Pan, Yutian, Zhang, Tianli, Zhong, Xiaomin, Long, Meixiao, Montone, Kathleen T., Tanyi, Janos L., Fan, Yi, Wang, Tian-Li, Shih, Ie-Ming, Hu, Xiaowen, Zhang, Lin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.02.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 38/39; 38/89; 45/88; 49/23; 49/91; 631/67; 631/67/69; 64/60; 692/699/67; Acetylation; Antineoplastic Agents - therapeutic use; Cancer; Cancer therapies; Chemotherapy; Copy number; Depletion; DNA Copy Number Variations - drug effects; Drug discovery; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genomes; Genomic analysis; Genomics; Genomics - methods; Histone Acetyltransferases - antagonists & inhibitors; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Histones - metabolism; Humanities and Social Sciences; Humans; Modulators; Molecular Targeted Therapy - methods; multidisciplinary; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Proteins; Science; Science (multidisciplinary); Target recognition; Therapeutic applications; Transcription; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08554-x

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. Targeting histone acetylation modulators (HAMPs) is a promising avenue of drug discovery in cancer research. Here, the authors integrate multi-dimensional genomic profiles to systematically investigate recurrent genomic alterations in HAMPs, identifying potential therapeutic targets for precision epigenetic treatment.