STRA13 Interacts with STAT3 and Modulates Transcription of STAT3-dependent Targets

Abstract

STRA13 is a pVHL-dependent bHLH transcription factor up-regulated on the mRNA level in multiple cancer cell lines and implicated recently in the regulation of immune cell homeostasis and autoimmunity. In searching for STRA13-interacting proteins with oncogenic potential by the yeast two-hybrid screening, we identified STAT3β as a STRA13-binding partner. We showed that STRA13 binds predominantly to phosphorylated (active) STAT3 α and β isoforms via its HLH and C-terminal regions. We also found that STRA13 was able to activate transcription from STAT-dependent cis-elements. Expression of endogenous STRA13 was shown to be cytokine-inducible, consistent with STRA13 involvement in STAT-dependent transcription regulation. We demonstrated that the STAT3-regulated promoter of the pro-apoptotic Fas gene was activated upon STRA13 over-expression and that co-expression of STRA13 with STAT3β or STAT3α modulated the transcriptional outcome. Forced expression of STRA13 induced apoptosis, in agreement with the STRA13 activation effect on the Fas promoter. Simultaneous expression of STRA13 and STAT3β resulted in alleviation of the STRA13 pro-apoptotic effect. Thus, for the first time, we identify STRA13 as a STAT3 partner and provide a consistent line of evidence for STRA13 involvement into regulation of apoptosis via the STAT pathways.