Abstract 5266: RYBP expression predicts survival of patients with hepatocellular carcinoma, and regulates response to chemotherapy

Abstract

Abstract RYBP (RING 1 and YY1-binding protein) is a newly identified member of the Polycomb group (PcG) proteins. PcG proteins are transcriptional repressors that epigenetically modify chromatin and participate in the establishment and maintenance of cell fates. These proteins are crucial for many biological processes, including self-renewal and differentiation, and cancer. Studies from our group and others suggest that RYBP has non-PcG functions and is downregulated in human cancers, including hepatocellular carcinoma (HCC). However, the potential role of RYBP in HCC is largely unknown. In the present study, for the first time, we systemically investigated the levels of RYBP expression and the linkage between RYBP deregulation and survivals of patients with HCC in 400 pairs of human HCC tissues and matched noncancerous samples. Using in vitro and in vivo HCC models, we determined the effort of RYBP on the survival of several HCC cell lines, including HepG2, Huh7 and Hep3B cells. We first verified that RYBP was downregulated in human HCC tumor specimens and cell lines, and that a low level of RYBP predicted a poor prognosis in HCC patients. We further demonstrated that enforced RYBP expression exerted potent effects against the various cell lines, leading to a significant decrease in cell viability, and inhibited cell colony formation and invasion, and induced apoptosis. We also found that the expression of numerous apoptosis- and metastasis-associated proteins was affected by RYBP. It reduced the expression of p53 in HepG2 cells, and increased Bax, cleaved-PARP and E-cadherin and, conversely, decreased Vimentin expression in all three HCC cells. Moreover, apoptosis was the main mechanism by which the RYBP exerted its cytostatic effects in HCC cells, while knockdown of RYBP showed opposite effects. In addition, we showed that AdRYBP infection inhibited the growth of tumors and induced RYBP expression in HepG2 and Huh7 xenograft models. There were no significant host toxicity and no gross organ abnormalities upon necropsy. We also determined that chemotherapeutic agents induced RYBP protein expression, and that RYBP sensitized HCC tumors to conventional chemotherapy through the induction of apoptosis both in vitro and in vivo. The results of these studies provide initial evidences supporting that the restoration of RYBP expression may be a new approach to targeted therapy for HCC and that RYBP may be a useful biomarker for predicting the prognosis of patients with HCC. (This work was supported by NIH/NCI grants R01 CA112029, R01 CA121211, and R01 CA186662 (to R.Z.); and NSFC 81272725 (to J.F.), NSFC 81372648 (to Q.G.) and Shanghai “Promising Youth Medical Worker” Project 13Y055 (to Q.G.) Citation Format: Wei Wang, Jianwen Cheng, Jiang-Jiang Qin, Sukesh Voruganti, Subhasree Nag, Jia Fan, Qiang Gao, Ruiwen Zhang. RYBP expression predicts survival of patients with hepatocellular carcinoma, and regulates response to chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5266. doi:10.1158/1538-7445.AM2015-5266