Browsing by Author "Riabowol, Karl Jr"

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    The Role of ING5 in Maintaining Stemness of Brain Tumor Initiating Cells
    (2016) Wang, Fangwu Jr; Riabowol, Karl Jr; Senger, Donna Jr; Cobb, Jennifer Jr; Rancourt, Derrick Jr
    Brain tumor initiating cells (BTICs) are believed to account for the recurrence of glioblastomas following treatment. Recent studies have shown that the stemness of BTICs and intratumoral differentiation hierarchy are determined largely on the epigenetic level. The ING family of epigenetic regulators function in diverse growth regulatory, metastasis and chemoresistance pathways, through targeting different histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes to the H3K4me3 mark to alter histone acetylation. ING5, a stoichiometric unit of three HAT complexes, has been directly implicated in the maintenance of epidermal stem cells. Here we found that ING5 was highly expressed in BTICs and rapidly downregulated upon in vitro differentiation. Ectopic expression of ING5 promoted self-renewal, prevented lineage differentiation and increased the stem cell pool in the BTIC population, accompanied by an elevated expression of stem cell core transcription factors OCT4, OLIG2 and Nestin. ING5 enhanced the activity of the PI3K/AKT and MEK/ERK pathways in the absence of growth factors to sustain self-renewal of BTICs over serial sphere passage. Transcriptome analysis indicated ING5 was an inducer of the intracellular calcium signaling and follicle stimulating hormone pathways, which were confirmed to co-operatively enhance the self-renewal of BTICs. This study identifies ING5 as a positive regulator of BTIC stem cell character, whose expression negatively correlates with patient prognosis, especially in the Proneural subtype and tumors with low SOX2 expression, therefore suggesting that altering histone acetylation status and the signaling pathways induced by ING5 may provide useful clinical targets to reduce recurrence in glioblastoma.