Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer

Sooryanarayana Varambally, Qi Cao, Ram Shankar Mani, Sunita Shankar, Xiaosong Wang, Bushra Ateeq, Bharathi Laxman, Xuhong Cao, Xiaojun Jing, Kalpana Ramnarayanan, J. Chad Brenner, Jindan Yu, Jung H. Kim, Bo Han, Patrick Tan, Chandan Kumar-Sinha, Robert J. Lonigro, Nallasivam Palanisamy, Christopher A. Maher, Arul M. Chinnaiyan

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Abstract

Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes and regulates the survival and metastasis of cancer cells. EZH2 is overexpressed in aggressive solid tumors by mechanisms that remain unclear. Here we show that the expression and function of EZH2 in cancer cell lines are inhibited by microRNA-101 (miR-101). Analysis of human prostate tumors revealed that miR-101 expression decreases during cancer progression, paralleling an increase in EZH2 expression. One or both of the two genomic loci encoding miR-101 were somatically lost in 37.5% of clinically localized prostate cancer cells (6 of 16) and 66.7% of metastatic disease cells (22 of 33). We propose that the genomic loss of miR-101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression.

Original languageEnglish (US)
Pages (from-to)1695-1699
Number of pages5
JournalScience
Volume322
Issue number5908
DOIs
StatePublished - Dec 12 2008

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    Varambally, S., Cao, Q., Mani, R. S., Shankar, S., Wang, X., Ateeq, B., Laxman, B., Cao, X., Jing, X., Ramnarayanan, K., Brenner, J. C., Yu, J., Kim, J. H., Han, B., Tan, P., Kumar-Sinha, C., Lonigro, R. J., Palanisamy, N., Maher, C. A., & Chinnaiyan, A. M. (2008). Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science, 322(5908), 1695-1699. https://doi.org/10.1126/science.1165395