Presentation Abstract

Abstract Number: 5348
Presentation Title: Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer
Presentation Time: Wednesday, Apr 10, 2013, 8:00 AM -12:00 PM
Location: Hall A-E, Poster Section 31
Poster Board Number: 01
Author Block: Irfan A. Asangani1, Bushra Ateeq1, Qi Cao1, Lois Dodson1, Mithil Pandhi1, Lakshmi P. Kunju1, Rohit Mehra1, Robert J. Lonigro1, Javed Siddiqui1, Nallasivam Palanisamy1, Yi-Mi Wu1, Xuhong Cao1, Jung H. Kim1, Mathew K. Iyer1, Christopher A. Maher1, Chandan Kumar-Sinha1, Sooryanarayana Varambally1, Arul M. Chinnaiyan1, Meng Zhao2, Zhaohui S. Qin2. 1University of Michigan, Ann Arbor, MI; 2Department of Statistics and Bioinformatics, Emory University, Atlanta, GA
Abstract Body: 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.