Abstract 4388: Targeted VHL activation by RNAa inhibits renal cell carcinoma

Abstract

Abstract Von Hippel Lindau (VHL) is a tumor suppressor protein classically known to target the α subunit of hypoxia inducible factor (HIF) for proteasomal degradation. Emerging evidence has underscored a novel role for VHL in both cell cycle regulation and extracelluar matrix assembly. Recent studies have reported that chemically synthesized small duplex RNAs complementary to target promoter sequence, also known as small activating RNA (saRNA), can specifically induce gene expression in cancer cells, which might be associated with epigenetic changes and exhibited long-lasting gene activation for nearly 2 weeks. In the present study, we designed 5 candidate dsRNAs (dsVHL-58, dsVHL-93, dsVHL-395, dsVHL-515 and dsVHL-675) targeted for the VHL promoter at sites ranging from -675 to -58 relative to the transcription start site. Compared with controls, dsVHL-675 induced VHL expression by approximately 10-fold in renal cell carcinoma 769-P (VHL methylated) cells. Transfection of a dsVHL-675 into 769-P cells significantly inhibited cell proliferation in dose dependent manner. In addition, single transfection of dsVHL-675 induced VHL gene expression for 14 days. Functional analysis of dsVHL-675 transfected cells revealed that dsVHL-675 induced apoptosis by activating caspase 3 in dose dependent manner. Knockdown experiments confirmed that induction of apoptosis by dsVHL-675 required Ago2 and TNRC6A. This study suggests that targeted activation of VHL by dsVHL-675 may be explored as a novel therapy for the treatment of renal cell carcinoma. Citation Format: Jong Soon Kang, Moo Rim Kang, Jieun Yun, Soo Jin Oh, Ki Hwan Park, Chang Woo Lee. Targeted VHL activation by RNAa inhibits renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4388. doi:10.1158/1538-7445.AM2014-4388