Abstract 3296: KLF9, a differentiation-associated transcription factor, suppresses Notch1 signaling and inhibits glioblastoma-initiating stem cells

Abstract

Abstract Tumor-initiating stem cells (alternatively called cancer stem cells, CSCs) are a subpopulation of tumor cells that plays unique roles in tumor propagation, therapeutic resistance and tumor recurrence. It is becoming increasingly important to understand the molecular signaling that regulates the self-renewal and differentiation of CSCs. Transcription factors are critical for the regulation of normal and neopolastic stem cells. The Krüppel-like family of transcription factors (KLFs) consists of 17 evolutionarily conserved zinc finger containing proteins with diverse regulatory functions. KLFs bind to GC-GT rich sites in gene promoter and enhancer regions and are known to contextually regulate the growth, proliferation, and differentiation of cells including non-neoplastic stem cells and cancer cells. Here, we examined the expression and function of KLF transcription factors in human glioblastoma (GBM)-drived neurosphere lines and low passage primary GBM-derived neurospheres that are enriched for tumor-initiating stem cells. We identify KLF9 as a relatively unique differentiation-induced transcription factor in GBM-derived neurospheres. KLF9 knockdown rescues GBM-derived neurospheres from Retinoic -acid-induced growth inhibition and differentiation. KLF9 induction is shown to induce neurosphere cell differentiation, inhibit neurosphere formation and deplete neurospheres of CD133+ stem-like cells. KLF9 induction also inhibits the growth of tumor xenografts established from GBM-derived neurospheres. We also show that KLF9 regulates GBM neurosphere cells by binding to the Notch1 promoter and suppressing Notch1 expression and downstream signaling. We compared the KLF9 expression between human GBM tumors and non-neoplastc human specimens. KLF9 is down regulated in human GBM tumors relative to normal brain. Our findings expand the role of KLF family members in stem cell and cancer biology, support KLF9 as a regulator of GBM malignancy, and as a potential biomarker and target for cancer therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3296. doi:10.1158/1538-7445.AM2011-3296