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

TLDR

EZH2 is a histone methyltransferase that epigenetically silences genes and promotes cancer cell survival and metastasis, yet its overexpression in aggressive tumors remains poorly understood. The authors aim to determine whether loss of miR‑101 drives EZH2 overexpression and epigenetic dysregulation that fuels cancer progression. They examined miR‑101 expression and genomic status in prostate cancer cell lines and patient tumors, linking miR‑101 loss to increased EZH2 activity. They found that miR‑101 expression declines during prostate cancer progression, its genomic loci are somatically deleted in 37.5 % of localized and 66.7 % of metastatic tumors, and this loss correlates with elevated EZH2 levels and inhibited EZH2 function in cell lines.

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.