Abstract 5348: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.5348-5348
• Main Authors: Asangani, Irfan A., Ateeq, Bushra, Cao, Qi, Dodson, Lois, Pandhi, Mithil, Kunju, Lakshmi P., Mehra, Rohit, Lonigro, Robert J., Siddiqui, Javed, Palanisamy, Nallasivam, Wu, Yi-Mi, Cao, Xuhong, Kim, Jung H., Iyer, Mathew K., Maher, Christopher A., Kumar-Sinha, Chandan, Varambally, Sooryanarayana, Chinnaiyan, Arul M., Zhao, Meng, Qin, Zhaohui S.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-5348

Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. EZH2 transcript expression levels were compared to all HMTases (n=51) in our compendium of RNA-seq data comprising 474 malignant and benign samples, representing 14 different tissue types. MMSET displayed the strongest correlation with EZH2 expression. Similarly, a meta-analysis of 1755 samples from 22 published microarray gene expression studies in Oncomine revealed co-expression of MMSET and EZH2 in 15 different cancers. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer. Citation Format: Irfan A. Asangani, Bushra Ateeq, Qi Cao, Lois Dodson, Mithil Pandhi, Lakshmi P. Kunju, Rohit Mehra, Robert J. Lonigro, Javed Siddiqui, Nallasivam Palanisamy, Yi-Mi Wu, Xuhong Cao, Jung H. Kim, Mathew K. Iyer, Christopher A. Maher, Chandan Kumar-Sinha, Sooryanarayana Varambally, Arul M. Chinnaiyan, Meng Zhao, Zhaohui S. Qin. Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5348. doi:10.1158/1538-7445.AM2013-5348