POZ Domain Transcription Factor Kaiso is a Downstream Effector of STAT1 for Multiple Myeloma Cell Survival and is also essential for Anoikis Resistance of Metastatic Solid Tumors

Abstract

Role of the transcription factor STAT1 in cancer cell survival has remained unclear. Here we document an oncogenic role for STAT1 in Multiple Myeloma (MM), wherein STAT1 regulates Kaiso expression, represses bmf and is essential for MM cell survival. Moreover, STAT1 is constitutively phosphorylated in MM cell lines and patient derived primary MM cells and STAT1-depletion resulted in reduced Kaiso levels. Importantly, expression of exogenous Kaiso rescued STAT1-depleted MM cells from apoptosis by reversing elevated BMF levels. Further, several MM cell lines harboring diverse oncogenic mutations rely on Kaiso for their survival revealing an oncogenic addiction to Kaiso in MM. Mechanistically, Kaiso interacts with and recruits HDAC1 to pro-apoptotic gene bmf promoter to maintain repressive state. In line with this, depletion of Kaiso or HDAC1 results in elevated BMF levels and apoptosis of MM cells. Kaiso is abundantly expressed in several MM cell lines and patient derived primary MM cells. Interestingly, Kaiso interacting partner p120-catenin levels are very low/undetectable in MM indicating that Kaiso function in MM is p120-independent. While previous reports suggested anoikis promoting role for Kaiso in breast cancer, we show here that bmf repression by Kaiso is central to anoikis-resistance of metastatic solid tumors. Collectively, our data indicate that Kaiso is a downstream effector for STAT1 in MM cell survival and that Kaiso mediated bmf repression is central to MM cell survival and anoikis resistance of metastatic solid tumors. Targetting Kaiso-mediated bmf repression would enable us to develop common drug for MM and metastasis of solid tumors.