Abstract C93: RYBP predicts survival of patients with non-small cell lung cancer and sensitizes chemotherapy

Abstract

Abstract Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and associates with a poor prognosis. Despite several targeted therapies have been developed with promising results, the therapeutic options for NSCLC are limited and the 5-year survival rate remains poor (∼15%). Therefore, there is an urgent need for a better understanding of its pathogenesis and exploring novel therapeutic targets. Ring1 and YY1 binding protein (RYBP) is a member of polycomb group (PcG) proteins that typically act as transcriptional repressors via epigenetic modification of chromatin and participate in the establishment and maintenance of cell fates. Recent studies have shown that RYBP also possesses PcG-independent functions that promote apoptosis and cell cycle arrest in cancer cells. Our previous study has shown that RYBP stabilizes p53 through inhibiting MDM2 activity. Recent study indicates that RYBP is downregulated in human cancers, including NSCLC, but the underlying mechanisms are largely unknown. The present study was designed to demonstrate the molecular role of RYBP in NSCLC development and progression, chemotherapy, and patient survival. We systemically investigated the expression of RYBP in human NSCLC tissues and matched non-cancerous samples and evaluated the associations between the RYBP expression in NSCLCs and patient survial. We also generated a replication-deficient recombinant adenovirus driving the expression of RYBP (Adv-RYBP) and carried out in vitro and in vivo studies to explore the molecular basis for the tumor suppressing role of RYBP in NSCLC. We first demonstrated that the RYBP mRNA and protein expressions levels were significantly down-regulated in NSCLC tissues compared with matched noncancerous lung tissues. The low expression of RYBP was significantly associated with the poor prognosis in NSCLC patients. We then identified that enforced RYBP expression decreased cell viability, inhibited colony formation and induced apoptosis in NSCLC cells, while RYBP knockdown led to the opposite effects. RYBP affected the expression of several apoptosis-related proteins; and promoting apoptosis was one of the main mechanisms of RYBP-mediated cell growth inhibition in NSCLC. Moreover, AdRYBP led to a decreased NSCLC tumor xenograft growth. Additionally, clinically used chemotherapeutic agents induced the expression of RYBP, and RYBP sensitized NSCLC cells to chemotherapy in vitro and in vivo. In conclusion, our results reveal that RYBP is a potential biomarker for the diagnosis and prognosis of NSCLC and that reactivating RYBP in cancer cells may provide an effective and safe therapeutic approach to NSCLC therapy. (Supported by NIH/NCI grants R01 CA186662). Citation Format: wei wang, Sukesh Voruganti, Jiang-Jiang Qin, Biyun Qian, Ruiwen Zhang. RYBP predicts survival of patients with non-small cell lung cancer and sensitizes chemotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C93.