Abstract 5433: XRCC5 promotes tumor growth and progression via PDK-1 signaling and predicts poor prognosis in melanoma

Abstract

Abstract Melanoma is one of the most malignant and aggressive cancers with high cancer-related deaths. Patients with melanoma are often diagnosed at an advanced stage that has developed local or even remote metastasis due to its inapparent symptoms at early stages. Melanoma is often insensitive to chemotherapies, and most patients that respond well to targeted therapies or immunotherapies at first will develop resistance within several months. Therefore, it is of urgency to better understand the mechanisms of melanoma tumorigenesis, and to discover novel molecular targets for its effective treatment. In this study, we identified XRCC5 as a potential therapeutic target by siRNA library screening in A375 melanoma cells. We found that knockdown of XRCC5 inhibited cell growth, migration and invasion, and induced apoptosis in melanoma cells. Conversely,overexpression of XRCC5 significantly promoted the growth, migration and invasion of melanoma cells. We next analyzed the global transcriptome in A375 cells with XRCC5 knockdown, and identified PDK-1 as a candidate gene regulated by XRCC5. Further investigation revealed that XRCC5 cooperated with HIF-1α to bind at the promoter of PDK-1, and enhanced the expression of PDK-1. Consistently, overexpression of PDK-1 rescued the cell growth inhibition caused by XRCC5 knockdown. Our clinical data showed that the expression of XRCC5 and PDK-1 were positively correlated and elevated in melanoma samples, and high expression of XRCC5 predicted poor prognosis in melanoma patients. Collectively, our study discovered that XRCC5 bound to the promoter of PDK-1 to activate its expression, which promoted melanoma growth and progression. Our results indicated that the XRCC5/PDK-1 pathway could be a potential therapeutic target for melanoma. Citation Format: Ge Qin, Tianze Liu, Wenbin Li, Yixin Li, Changlin Zhang, Qian Long, Dingbo Shi, Miao Chen, Shuting Huang, Wuguo Deng. XRCC5 promotes tumor growth and progression via PDK-1 signaling and predicts poor prognosis in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5433.