Inhibition of EZH2 exerts antitumorigenic effects in renal cell carcinoma via LATS1

Abstract

The most common type of kidney cancer in adults is renal cell carcinoma (RCC), which accounts for approximately 90% of cases. RCC is a variant disease with numerous subtypes; the most common subtype is clear cell RCC (ccRCC, 75%), followed by papillary RCC (pRCC, 10%) and chromophobe RCC (chRCC, 5%). To identify a genetic target for all subtypes, we analyzed The Cancer Genome Atlas (TCGA) databases of ccRCC, pRCC, and chromophobe RCC. Enhancer of zeste homolog 2 (EZH2), which encodes a methyltransferase, was observed to be significantly upregulated in tumors. The EZH2 inhibitor tazemetostat induced anticancer effects in RCC cells. TCGA analysis revealed that large tumor suppressor kinase 1 (LATS1), a key tumor suppressor of the Hippo pathway, was significantly downregulated in tumors; the expression of LATS1 was increased by tazemetostat. Through additional experiments, we confirmed that LATS1 plays a crucial role in EZH2 inhibition and has a negative association with EZH2. Therefore, we suggest that epigenetic control could be a novel therapeutic strategy for three subtypes of RCC.

Keywords

• EZH2
• Hippo pathway
• LATS1
• renal cell carcinoma
• tazemetostat