MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B

Abstract

SUMMARY The hypoxic tumor microenvironment serves as a niche for maintaining the glioma-initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence. Here we report that hypoxia-induced miR-215 is vital for reprograming GICs to fit the hypoxic microenvironment via suppressing the expression of an epigenetic regulator KDM1B and modulating activities of multiple pathways. Interestingly, biogenesis of miR-215 and several miRNAs is accelerated post-transcriptionally by hypoxia-inducible factors (HIFs) through HIF-Drosha interaction. Moreover, miR-215 expression correlates inversely with KDM1B while positively with HIF1α and GBM progression in patients. These findings reveal a direct role of HIF in regulating miRNA biogenesis and consequently activating the miR-215-KDM1B-mediated signaling required for GIC adaptation to hypoxia.

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“…Nowadays many new therapies for glioma such as immunotherapy and gene therapy are constantly emerging, which are expected to further improve the prognosis of patients with glioma (Jiang et al, 2015). CD164 is a sialic acid mucin located on the No.6 chromosome (Hu et al, 2016).Studies have shown that CD164 played a role in regulating the growth, apoptosis and invasive behavior of solid tumors such as colon cancer, cervical cancer and medulloblastoma (Forde et al, 2007) ; (Shi et al, 2014). The research results showed that CD164 can be used as a molecular biological marker for acute lymphoblastic leukemia (Coustan-Smith et al, 2011).…”

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“…Nowadays many new therapies for glioma such as immunotherapy and gene therapy are constantly emerging, which are expected to further improve the prognosis of patients with glioma (Jiang et al, 2015). CD164 is a sialic acid mucin located on the No.6 chromosome (Hu et al, 2016).Studies have shown that CD164 played a role in regulating the growth, apoptosis and invasive behavior of solid tumors such as colon cancer, cervical cancer and medulloblastoma (Forde et al, 2007) ; (Shi et al, 2014). The research results showed that CD164 can be used as a molecular biological marker for acute lymphoblastic leukemia (Coustan-Smith et al, 2011).…”

The role of micro-RNA in the regulation of signal pathways in gliomas

“…Среди мишеней miR-215 в ОСК глиобластомы имеется мРНК KDM1B (lysine demethylase 1B) из семейства JMJC [85]. Следует отметить, что гистоновые деметилазы JMJC могут быть другой патогенетически значимой мишенью (R)-2HG: in vitro 2-гидроксиглутарат блокирует многие 2-оксоглутарат-зависимые ферменты, в том числе гистоновые деметилазы KDM2A, KDM4A, KDM4C, KDM7A [74].…”

“…Нокдаун KDM1B усиливал формирование нейросфер, экспрессию генов, ассоциированных с метаболизмом глюкозы, в субпопуляции ОСК; сниженная экспрессия KDM1B в тканях глиобластомы пациентов коррелировала с увеличенной экспрессией HIF1A и miR-215 и с неблагоприятным прогнозом. HIF1a, уровень которого увеличивается при гипоксии в ОСК глиобластомы, взаимодействует с Drosha-комплексом pri-miR-215, а сайленсинг HIF1a предотвращает гипоксия-индуцированное увеличение экспрессии miR-215 [85]. Другая деметилаза -KDM1A (lysine demethylase 1A) -является прямой мишенью miR-329 при нейробластоме; при этом уровень этой опухоль-супрессорной miR-329 понижается при нейробластоме [86].…”