X-linked inhibitor of apoptosis protein (XIAP) is important in the regulation of cancer cell biological behaviors. However, little is known about the molecular mechanism by which the XIAP domains promote aggressive tumor behavior in human bladder cancer (BC). Herein, we discovered that ectopic expression of the BIR domains of XIAP rescued the MMP2 activation and human BC invasion in human BC cells with XIAP deletion. Interestingly, Src expression was upregulated in XIAP/BIR domain-deficient cells, whereas restoration of BIR domain in XIAP-deletion cells recused Src expression. Moreover, knockdown of Src reversed the defects of MMP2 activation and BC invasion in XIAP-deficient BC cells, revealing that Src acts as a XIAP downstream negative regulator for MMP2 activation and BC invasion. Mechanistic studies revealed that the regulatory effect of the BIR domains of XIAP on Src expression was due to directly inhibition of its protein translation by upregulation of miR-203 resulting from activation of the transcription factors Sp1 and E2F1, while the BIR domains of XIAP was found to interact with both Sp1 and E2F1 to activate these transcription factors. Overall, our studies demonstrate that BIR domain of XIAP is able to bind to Sp1 and E2F1 leading to their transcriptional activation, resulting their targeted miR-203 transcription, consequently directly targets the 3'-UTR of src mRNA and therefore attenuating SRC protein translation, and activating MMP2 and BC invasion.

Citation Format: Xiaohui Hua, Jiheng Xu, Honglei Jin, Chuanshu Huang. Interaction of BIR domain of XIAP with Sp1/E2F1 activates MMP2 and bladder cancer cell invasion by inhibiting src protein translation [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 107.