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ANP32B deficiency impairs proliferation and suppresses tumor progression by regulating AKT phosphorylation.

ABSTRACT: The acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) is reported to impact normal development, with Anp32b-knockout mice exhibiting smaller size and premature aging. However, its cellular and molecular mechanisms, especially its potential roles in tumorigenesis, remain largely unclear. Here, we utilize 'knockout' models, RNAi silencing and clinical cohorts to more closely investigate the role of this enigmatic factor in cell proliferation and cancer phenotypes. We report that, compared with Anp32b wild-type (Anp32b(+/+)) littermates, a broad panel of tissues in Anp32b-deficient (Anp32b(-/-)) mice are demonstrated hypoplasia. Anp32b(-/-) mouse embryo fibroblast cell has a slower proliferation, even after oncogenic immortalization. ANP32B knockdown also significantly inhibits in vitro and in vivo growth of cancer cells by inducing G1 arrest. In line with this, ANP32B protein has higher expression in malignant tissues than adjacent normal tissues from a cohort of breast cancer patients, and its expression level positively correlates with their histopathological grades. Moreover, ANP32B deficiency downregulates AKT phosphorylation, which involves its regulating effect on cell growth. Collectively, our findings suggest that ANP32B is an oncogene and a potential therapeutic target for breast cancer treatment.

SUBMITTER: Yang S

PROVIDER: S-EPMC4849165 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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ANP32B deficiency impairs proliferation and suppresses tumor progression by regulating AKT phosphorylation.

Yang S S Zhou L L Reilly P T PT Shen S-M SM He P P Zhu X-N XN Li C-X CX Wang L-S LS Mak T W TW Chen G-Q GQ Yu Y Y

Cell death & disease 20160204

The acidic leucine-rich nuclear phosphoprotein 32B (ANP32B) is reported to impact normal development, with Anp32b-knockout mice exhibiting smaller size and premature aging. However, its cellular and molecular mechanisms, especially its potential roles in tumorigenesis, remain largely unclear. Here, we utilize 'knockout' models, RNAi silencing and clinical cohorts to more closely investigate the role of this enigmatic factor in cell proliferation and cancer phenotypes. We report that, compared wi ...[more]

PMID: 26844697

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Project description:Simple Summary Human glioblastoma is the most common and malignant primary brain tumor and is universally fatal. Currently, there is no cure for the disease. One major hurdle to developing effective therapies against GBM has been our lack of understanding of regulators of crucial processes and features that define and sustain tumor cells. This study reveals a novel role of transcription factor TCF12 in the regulation of proliferation in GBM tumors using human patient-derived cell lines and an in vivo mouse GBM model. We find that TCF12 deficiency impairs the proliferation of tumor cells in vitro and slows tumor growth in vivo resulting in improved overall survival. We also find that TCF12 regulates the expression of some key regulators of the cell cycle in tumor cells. Abstract Isocitrate dehydrogenase (IDH)-wild-type glioblastoma (GBM) is the most common and aggressive primary brain tumor which carries a very poor overall prognosis and is universally fatal. Understanding the transcriptional regulation of the proliferation of GBM tumor cells is critical for developing novel and effective treatments. In this study, we investigate the role of the transcription factor TCF12 in the regulation of GBM proliferation using human and murine GBM cell lines and an in vivo GBM xenograft model. Our study shows that TCF12 deficiency severely impairs proliferation of tumor cells in vitro by disrupting/blocking the G1 to S phase transition. We also discover that TCF12 loss significantly improves animal survival and that TCF12-deficient tumors grow much slower in vivo. Overexpression of TCF12, on the other hand, leads to an increase in the proliferation of tumor cells in vitro and more aggressive tumor progression in vivo. Interestingly, loss of TCF12 leads to upregulation of signature genes of the oligodendrocytic lineage in GBM stem cells, suggesting a role for TCF12 in inhibiting differentiation along the oligodendrocytic lineage. Transcriptomic data also reveals that loss of TCF12 leads to dysregulation of the expression of key genes in the cell cycle. Our work demonstrates critical roles of TCF12 in GBM tumor progression.

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ANP32B deficiency impairs proliferation and suppresses tumor progression by regulating AKT phosphorylation.

Publications

ANP32B deficiency impairs proliferation and suppresses tumor progression by regulating AKT phosphorylation.

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