Title: The RING domain in the anti-apoptotic protein XIAP stabilizes c-Myc protein and preserves anchorage-independent growth of bladder cancer cells.
Authors: Jiang, Guosong; Huang, Chao; Liao, Xin; Li, Jingxia; Wu, Xue-Ru; Zeng, Fuqing; Huang, Chuanshu
Published In J Biol Chem, (2019 04 12)
Abstract: X-linked inhibitor of apoptosis protein (XIAP) suppresses apoptosis and plays key roles in the development, growth, migration, and invasion of cancer cells. Therefore, XIAP has recently attracted much attention as a potential antineoplastic therapeutic target, requiring elucidation of the molecular mechanisms underlying its biological activities. Here, using shRNA-mediated gene silencing, immunoblotting, quantitative RT-PCR, anchorage-independent growth assay, and invasive assay, we found that XIAP's RING domain, but not its BIR domain, is crucial for XIAP-mediated up-regulation of c-Myc protein expression in human bladder cancer (BC) cells. Mechanistically, we observed that the RING domain stabilizes c-Myc by inhibiting its phosphorylation at Thr-58 and that this inhibition is due to activated ERK1/2-mediated phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser-9. Functional studies further revealed that c-Myc protein promotes anchorage-independent growth and invasion stimulated by the XIAP RING domain in human BC cells. Collectively, the findings in our study uncover that the RING domain of XIAP supports c-Myc protein stability, providing insight into the molecular mechanism and role of c-Myc overexpression in cancer progression. Our observations support the notion of targeting XIAP's RING domain and c-Myc in cancer therapy.
PubMed ID: 30819803
MeSH Terms: Cell Line, Tumor; Gene Expression Regulation, Neoplastic*; Glycogen Synthase Kinase 3 beta/genetics; Glycogen Synthase Kinase 3 beta/metabolism; Humans; Neoplasm Invasiveness/genetics; Phosphorylation/genetics; Protein Domains; Protein Stability; Proto-Oncogene Proteins c-myc/biosynthesis*; Proto-Oncogene Proteins c-myc/genetics; Urinary Bladder Neoplasms/genetics; Urinary Bladder Neoplasms/metabolism*; Urinary Bladder Neoplasms/pathology; X-Linked Inhibitor of Apoptosis Protein/genetics; X-Linked Inhibitor of Apoptosis Protein/metabolism*