Abstract 5159: Kruppel-like factor 9 modulates the growth and differentiation of glioblastoma-derived neoplastic stem cells

Abstract

Listen

Translate article

Abstract Glioblastoma (GBM) is the most prevalent brain tumor with high frequency of recurrence. During the past decade, the identification of neoplastic stem-like cells in diverse human cancers including GBM represents an important conceptual advance in cancer biology and suggests new therapeutic strategies. We found that retinoic acid (RA) induces growth arrest and cell differentiation of GBM-derived stem-like cells (GBM-SCs). RA treatment also inhibited the growth of GBM-SC xenografts in mice. We studied gene expression changes during RA-induced GBM-SC differentiation and found that kruppel-like factor 9 (KLF9) expression increased 8-fold after RA treatment. KLF proteins are evolutionarily conserved zinc finger-containing transcription factors that bind to GC-rich DNA regions. KLF9 is known to function as a progesterone receptor cofactor to regulate progesterone-responsive genes but its function in cancer and stem cell biology is essentially unknown. We used lentivirus-based methods to modulate KLF9 expression in GBM-SCs. KLF9 gain-of-function induced GBM-SC differentiation and inhibited GBM-derived neurosphere formation in clonogenic and neurosphere cell growth assays. KLF9 gain-of-function also prevented the growth of GBM-SC subcutaneous xenografts in mice. Knockdown of KLF9 suppressed RA-induced differentiation of GBM-SCs. These data indicate that KLF9 and possibly other KLF family members modulate transcriptional mechanisms that regulate GBM-SC growth, differentiation, and possibly tumor initiation. Currently, we are utilizing gene expression microarray and chromatin immunoprecipitation assays to study the KLF9 target genes. Our findings provide new insights pertaining to the molecular regulation of the GBM-SC phenotype and could lead to innovative therapeutic strategies for targeting the stem-like cell pool in malignant brain tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5159.