The enhancer of zeste homolog 2 gene contributes to cell proliferation and apoptosis resistance in renal cell carcinoma cells

Abstract

The enhancer of zeste homolog 2 (EZH2) gene has been recently linked to human malignancies where it may serve as a new target for cancer therapy. Here, we analyzed EZH2 expression in primary renal cell carcinoma (RCC) specimens and in nontumorous tissue samples from adult kidney. EZH2 transcripts were detectable in all RCC specimens examined. Expression levels were significantly higher in tumor tissue (p 0.0001) than in samples from normal adult kidney. Moreover, inhibition of endogenous EZH2 expression in RCC cell lines by RNA interference (RNAi) led to reduced proliferation and increased apoptosis in RCC cells. These data show that EZH2 is overexpressed in RCC. Furthermore, they indicate that the EZH2 gene plays a role for both the proliferation and the apoptosis resistance of RCC cells. Targeted inhibition of EZH2 could therefore represent a novel strategy to improve the therapeutic response of RCC. ' 2008 Wiley-Liss, Inc.Key words: renal cell carcinoma; enhancer of zeste homolog 2 (EZH2); RNA interference; tumor therapy Renal cell carcinoma (RCC) is estimated to account for more than 51,000 new cases and almost 13,000 cancer-related deaths in the United States in 2007, making it the second most lethal of the urological cancers. 1 RCCs typically are highly resistant toward chemotherapy with a concomitant poor prognosis in advanced stages. 2 Therefore, the identification of novel therapeutic targets and the development of new strategies for RCC treatment are urgently required.The enhancer of zeste homolog 2 (EZH2) gene encodes a polycomb group (PcG) protein, which acts as a histone methyltransferase 3-5 and also can directly control DNA methylation. 6 EZH2 is involved in several key regulatory mechanisms within eukaryotic cells, such as control of embryonal development or cell proliferation. 7,8 Moreover, there is accumulating evidence indicating that EZH2 may also play a pivotal role in the etiology of several tumor forms, which include prostate cancer 9,10 and breast cancer. 10,11 For both of these cancers, EZH2 expression is often observed in proliferative and more aggressive tumor subgroups and has diagnostic and/or prognostic value. [9][10][11] Notably, however, EZH2 appears to be not only a potential tumor marker but may itself contribute to the deregulation of cell growth as a bona fide oncogene. Overexpression of EZH2 conferred cellular growth advantage in vitro, 11-13 promoted invasion 11 and exhibited oncogenic properties in nude mice. 14 Vice versa, inhibition of EZH2 expression by antisense constructs or RNA interference (RNAi) did result in growth inhibition of some cancer cells. 9,15 Furthermore, RNAi-mediated inhibition of EZH2 expression induced anoikis in circulating prostate carcinoma precursor cells 16 and apoptotic cell death in breast cancer cells. 17 A possible role of EZH2 for RCC has not been studied so far. Here, we analyzed EZH2 expression in primary RCC specimens and in nontumorous tissue. In addition, we investigated the functional role of EZH2 for the proliferation control and apop...

Sunitinib Dose Escalation Overcomes Transient Resistance in Clear Cell Renal Cell Carcinoma and Is Associated with Epigenetic Modifications

“…Previous studies have shown that epigenetic changes including differential expression of the histone methyltransferase EZH2 may be associated with drug resistance (17-18). A survey of over 400 ccRCC tumors from the TCGA data portal identified several changes in the methylation status of the lysine tails of histone 3 and the associated mutated genes with progression of disease to advance staged (19).…”

PBRM1 and BAP1 as Novel Targets for Renal Cell Carcinoma

“…52 Knock-down of EZH2 reduces cell proliferation, 52 and causes apoptosis in a subset of RCC cell lines. 51, 52 Given the low mutation frequency of SMARCB1 it is unlikely that SMARCB1 was the determinant of sensitivity in these cell lines. Of note, the one cell line that did not undergo apoptosis in response to EZH2 knock-down, 769-P, 51 is BAP1 mutant.…”

“…51, 52 Given the low mutation frequency of SMARCB1 it is unlikely that SMARCB1 was the determinant of sensitivity in these cell lines. Of note, the one cell line that did not undergo apoptosis in response to EZH2 knock-down, 769-P, 51 is BAP1 mutant. 18 EZH2 levels in ccRCC may have prognostic value, but these data are controversial.…”

“…Of note, EZH2 expression is upregulated in RCC compared to paired normal renal tissues, 51 and EZH2 is on chromosome 7q36.1, a region amplified in 13% of ccRCC. 52 Knock-down of EZH2 reduces cell proliferation, 52 and causes apoptosis in a subset of RCC cell lines.…”

The Role of microRNAs in the Regulation of Apoptosis in Lung Cancer and Its Application in Cancer Treatment

“…Increasing evidence has revealed that EZH2 has oncogenic properties, as an increased expression of EZH2 augments proliferation and invasion of cancer cells [92–94], while depletion leads to a decline in cell proliferation, increased apoptosis, and inhibition of metastatic tumor growth in vivo [95, 96]. Overexpression of EZH2 has been associated with tumor progression and cancer aggressiveness in NSCLC [97].…”