Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3. The role of the H3.3K27M mutation in tumorigenesis not fully understood. Here, we use a human embryonic stem cell system to model this tumor. We show that H3.3K27M expression synergizes with p53 loss and PDGFRA activation in neural progenitor cells derived from human embryonic stem cells, resulting in neoplastic transformation. Genome-wide analyses indicate a resetting of the transformed precursors to a developmentally more primitive stem cell state, with evidence of major modifications of histone marks at several master regulator genes. Drug screening assays identified a compound targeting the protein menin as an inhibitor of tumor cell growth in vitro and in mice.

Cancer stem cells are believed to be responsible for tumor initiation and development. Much current research on human brain tumors is focused on the stem-like properties of glioblastoma stem cells (GSCs). However, little is known about the molecular mechanisms of cell cycle regulation that discriminate between GSCs and differentiated glioblastoma cells. Here we show that cyclin D2 is the cyclin that is predominantly expressed in GSCs and suppression of its expression by RNA interference causes G1 arrest in vitro and growth retardation of GSCs xenografted into immunocompromised mice in vivo. We also demonstrate that the expression of cyclin D2 is suppressed upon serum-induced differentiation similar to what was observed for the cancer stem cell marker CD133. Taken together, our results demonstrate that cyclin D2 has a critical role in cell cycle progression and the tumorigenicity of GSCs.

Glioblastoma is one of the most aggressive forms of cancers and has a poor prognosis. Genomewide analyses have revealed that a set of core signaling pathways, the p53, RB, and RTK pathways, are commonly deregulated in glioblastomas. However, the molecular mechanisms underlying the tumorigenicity of glioblastoma are not fully understood. Here, we show that the lysine deacetylase SIRT2 is required for the proliferation and tumorigenicity of glioblastoma cells, including glioblastoma stem cells. Furthermore, we demonstrate that SIRT2 regulates p73 transcriptional activity by deacetylation of its C-terminal lysine residues. Our results suggest that SIRT2-mediated inactivation of p73 is critical for the proliferation and tumorigenicity of glioblastoma cells and that SIRT2 may be a promising molecular target for the therapy of glioblastoma.

Abstract. ptprd is a receptor-type tyrosine-protein phosphatase. recent analyses of comprehensive mutations and copy numbers have revealed that PTPRD is frequently mutated and homozygously deleted in various types of cancer, including glioblastoma, melanoma, breast and colon cancer. however, the molecular functions of ptprd in cancer progression have yet to be elucidated. herein, ptprd suppressed colon cancer cell migration and was required for appropriate cellcell adhesion. in addition, ptprd regulated cell migration in cooperation with β-catenin/tcF signaling and its target cd44. Furthermore, expression levels of ptprd were down-regulated in highly invasive cancers and were significantly correlated with patient survival. Our findings suggest that PTPRD is required for colon cancer invasion and progression. Introductionreceptor-type tyrosine-protein phosphatase δ (ptprd) is a receptor type tyrosine-protein phosphatase (rptp) that is composed of a cell adhesion molecule-like extracellular domain and two cytoplasmic protein tyrosine phosphatase (ptp) domains (1,2). ptprd is predominantly expressed in the brain and is known to be involved in the guidance and termination of motor neurons during embryonic development (3). ptprd knockout mice exhibit impaired learning and memory, also indicating that ptprd is essential for the organization of neural circuits (4).it has been shown that PTPRD is frequently mutated in various types of cancer, including lung, colon cancer and glioblastoma (5-8). Furthermore, homozygous deletions and epigenetic silencing of PTPRD are also found in these cancers, indicating that PTPRD is a tumor-suppressor gene (9-11).however, the molecular functions of ptprd in cancer progression are not fully understood.the extracellular domain of ptprd was reported to enhance neurite outgrowth in an isoform-specific manner (12). the intracellular domain of ptprd interacts with cytoskeletal rearrangement factors, such as the liprin-α family of proteins and mim (missing in metastasis, also known as mtSS1) (13-15). these observations indicate that ptprd regulates the adhesion and migration of cancer cells and that the loss of ptprd function promotes cancer progression. in the present study, ptprd suppressed colon cancer cell migration and was found to be required for appropriate cell-cell adhesion. ptprd also regulated cell migration in cooperation with β-catenin/tcF signaling and its target cd44. cd44 is a receptor for hyaluronic acid and other extracellular matrix (Ecm) proteins, and is reported to be involved in cancer invasion and metastasis (16). Furthermore, the expression levels of ptprd were decreased in highly invasive cancers compared to less invasive cases, and were significantly correlated with patient survival. these results implicate ptprd in colon cancer cell invasion and progression. Materials and methodsCell culture and transfection. dld-1 cells were cultured in rpmi medium supplemented with 10% fetal bovine serum (FBS). HEK293T cells were cultured in Dulbecco's modified Eagle's medium (dm...