FoxG1 Interacts with Bmi1 to Regulate Self-Renewal and Tumorigenicity of Medulloblastoma Stem Cells

Abstract

Brain tumors represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant tumor. Recent studies have demonstrated the presence of several MB molecular subgroups, each distinct in terms of prognosis and predicted therapeutic response. Groups 1 and 2 are characterized by relatively good clinical outcomes and activation of the Wnt and Shh pathways, respectively. In contrast, groups 3 and 4 (''non-Shh/Wnt MBs'') are distinguished by metastatic disease, poor patient outcome, and lack a molecular pathway phenotype. Current gene expression platforms have not detected brain tumor-initiating cell (BTIC) selfrenewal genes in groups 3 and 4 MBs as BTICs typically comprise a minority of tumor cells and may therefore go undetected on bulk tumor analyses. Since increasing BTIC frequency has been associated with increasing tumor aggressiveness and poor patient outcome, we investigated the subgroup-specific gene expression profile of candidate stem cell genes within 251 primary human MBs from four nonoverlapping MB transcriptional databases (Amsterdam, Memphis, Toronto, Boston) and 74 NanoString-subgrouped MBs (Vancouver). We assessed the functional relevance of two genes, FoxG1 and Bmi1, which were significantly enriched in non-Shh/Wnt MBs and showed these genes to mediate MB stem cell self-renewal and tumor initiation in mice. We also identified their transcriptional regulation through reciprocal promoter occupancy in CD151 MB stem cells. Our work demonstrates the application of stem cell data gathered from genomic platforms to guide functional BTIC assays, which may then be used to develop novel BTIC self-renewal mechanisms amenable to therapeutic targeting.

Prognostic Value of Polycomb Proteins EZH2, BMI1 and SUZ12 and Histone Modification H3K27me3 in Colorectal Cancer

“…In this study, we investigated the expression of three PcG proteins (EZH2, BMI1 and SUZ12) and associated histone modification H3K27me3 in colorectal cancer tissues. Aberrant expression of each of these histone-modifying enzymes, and of histone modification H3K27me3, has been indicated to contribute to tumorigenesis in several types of cancer and has been correlated to patient outcome [11]–[24]. Studies in literature show conflicting results regarding the prognostic value of the Polycomb group proteins in colorectal cancer.…”

“…Aberrant expression of several PcG proteins and correlations with patient outcome have been reported in various cancers. For example, expression of BMI1 polycomb ring finger oncogene (BMI1), a component of PRC1 and an important factor in stem cells [11], [12], was found to be correlated to patient outcome in several types of cancer [13]–[16]. Enhancer of zeste homolog 2 (EZH2), a key protein in the PRC2 complex, was also found to have prognostic value in several types of cancer [17]–[20].…”

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

“…One involves multiple miRNA families known as regulators of p21 mRNA, playing a key role in governing the G1/S transition and cell cycle checkpoint in undifferentiated human embryonic SCs [39]. The other is mediated by transcription factors such as Bmi1, FoxG1, and Olig2, strong repressors of p21, promoting amplification of NSCs and often overexpressed in brain tumors [40][41][42][43][44].…”

Bmi1 – A Path to Targeting Cancer Stem Cells

“…62 Clinically, increased Bmi1 expression levels have been shown to correlate with poor patient prognosis in several aggressive cancer types, including colorectal carcinoma, 63 GBM, 64 and medulloblastoma. 65 The maintenance of self-renewal potential by Bmi1 contributes to the aggressive cancer phenotype by allowing CSCs to evade chemoradiotherapy regimens and drive tumour recurrence. Further contributions of Bmi1 to cancer cell survival through therapy has come from its role in promoting DNA damage repair.…”