Submitted on September 3, 2008
Accepted on November 3, 2008

Genomic Loss of microRNA-101 Leads to Overexpression of Histone Methyltransferase EZH2 in Cancer

Sooryanarayana Varambally ¹, Qi Cao ², Ram-Shankar Mani ², Sunita Shankar ², Xiaosong Wang ², Bushra Ateeq ², Bharathi Laxman ², Xuhong Cao ³, Xiaojun Jing ², Kalpana Ramnarayanan ⁴, J. Chad Brenner ⁵, Jindan Yu ², Jung H. Kim ², Bo Han ², Patrick Tan ⁶, Chandan Kumar-Sinha ², Robert J. Lonigro ⁷, Nallasivam Palanisamy ⁸, Christopher A. Maher ², Arul M. Chinnaiyan ^9*

¹ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁴ National Cancer Centre, Singapore.
⁵ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁶ National Cancer Centre, Singapore.; Genome Institute of Singapore, Singapore.
⁷ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁸ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; National Cancer Centre, Singapore.
⁹ Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Department of Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

^* To whom correspondence should be addressed.
Arul M. Chinnaiyan , E-mail: arul{at}umich.edu

These authors contributed equally to this work.

Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes and that 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 is 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 cancers (6/16) and 66.7% of metastatic disease (22/33). We propose that genomic loss of miR-101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression.