Epigenetic inactivation of HOXA11, a novel functional tumor suppressor for renal cell carcinoma, is associated with RCC TNM classification

Abstract

Epigenetic inactivation of HOXA11, a putative tumor suppressor, is frequently observed in a number of solid tumors, but has not been described in RCC (renal cell carcinoma). In this study, we investigated the expression, epigenetic changes and the function of HOXA11 in human renal cell carcinoma (RCC). HOXA11 was silenced or down-regulated in RCC cell lines and tissues. Methylation specific PCR (MSP) and bisulfite genomic sequencing (BGS) revealed that the HOXA11 promoter was hypermethylated in 5/6 RCC cell lines. Demethylation treatment resulted in demethylation of the promoter and increased HOXA11 expression in these cell lines. HOXA11 methylation was also detected in 68/95 (70.5%) primary RCC tumors, but only rare adjacent non-malignant renal tissues (13%, 3/23) showed hypermethylation of promoter. We also found that the methylation of HOXA11 was associated with higher TNM classification of RCC (p<0.05). Ectopic expression of HOXA11 led to significant inhibition of proliferation, colony formation, migration and invasion abilities and induced RCC cells apoptosis. Moreover, HOXA11 was found to inhibit Wnt signaling. Thus, our study demonstrated that HOXA11 function as a tumor suppressor in RCC, while it is frequently silenced by promoter methylation in RCC.