ING5 activity in self-renewal of glioblastoma stem cells via calcium and follicle stimulating hormone pathways

Abstract

Stem cell-like brain tumor initiating cells (BTICs) cause recurrence of glioblastomas, with BTIC ‘stemness’ affected by epigenetic mechanisms. The ING family of epigenetic regulators (ING1-5) function by targeting histone acetyltransferase (HAT) or histone deacetylase complexes to the H3K4me3 mark to alter histone acetylation and subsequently, gene expression. Here we find that ectopic expression of ING5, the targeting subunit of HBO1, MOZ and MORF HAT complexes increases expression of the Oct4, Olig2 and Nestin stem cell markers, promotes self-renewal, prevents lineage differentiation and increases stem cell pools in BTIC populations. This activity requires the plant homeodomain region of ING5 that interacts specifically with the H3K4me3 mark. ING5 also enhances PI3K/AKT and MEK/ERK activity to sustain self-renewal of BTICs over serial passage of stem cell-like spheres. ING5 exerts these effects by activating transcription of calcium channel and follicle stimulating hormone pathway genes. In silico analyses of The Cancer Genome Atlas data suggest that ING5 is a positive regulator of BTIC stemness, whose expression negatively correlates with patient prognosis, especially in the Proneural and Classical subtypes, and in tumors with low SOX2 expression. These data suggest that altering histone acetylation status and signaling pathways induced by ING5 may provide useful clinical strategies to target tumor resistance and recurrence in glioblastoma.

NFAT1-Mediated Regulation of NDEL1 Promotes Growth and Invasion of Glioma Stem-like Cells

“…S4C-S4F). These results are consistent with previous reports that both NFAT1 and NDEL1 are associated with the activation of Erk (29,30), which plays an important role in the stemness maintenance of GSCs (31,32). In addition, blocking Erk activation using the inhibitor SCH772984 reduced the viability, invasion, self-renewal, and levels of stemness markers in NFAT1-OE G03-GSCs (Supplementary Fig.…”

Cell Calcium Imaging as a Reliable Method to Study Neuron–Glial Circuits

“…ING5, a member of the ING family of epigenetic regulators that alter histone acetylation and, subsequently, gene expression, increased the expression of stem cell markers and, consequently, brain tumor-initiating cells that cause the recurrence of glioblastomas (stemness) affected by epigenetic mechanisms ( Wang F. et al, 2018 ). Proteomics and cell imaging assays demonstrated that ING5-transfected cells had intracellular Ca 2+ elevation, which was associated with self-renewal, due to an increased expression of several types of Ca 2+ channels, like L-type and P/Q-type voltage-gated Ca 2+ channels, and TRPC ( Wang F. et al, 2018 ). Differentiated glioblastoma cells constitute a distinctive niche compared to glioblastoma stem cells, sending cues to the microenvironment, both as juxtacrine (involving direct contact) or paracrine (through secreted factors).…”

<p>Delivery luteolin with folacin-modified nanoparticle for glioma therapy</p>

“…Glioblastoma mutliforme (GBM) is the most common and has the poorest prognosis of any malignant tumor of the central nervous system, which is classified as the fourth stage by WHO. [1][2][3][4] It turns out that the morbidity of GBM among people is as high as 3.19/100,000 through age adjustment by Central Brain Tumor Registry of the United States (CBTRUS). GBM accounts for 45.2% of all primary central nervous system malignant neoplasms and a high 54% of glioma's.…”