ELK4 neutralization sensitizes glioblastoma to apoptosis through downregulation of the anti-apoptotic protein Mcl-1

Abstract

Glioma is the most common adult primary brain tumor. Its most malignant form, glioblastoma multiforme (GBM), is almost invariably fatal, due in part to the intrinsic resistance of GBM to radiation- and chemotherapy-induced apoptosis. We analyzed B-cell leukemia-2 (Bcl-2) anti-apoptotic proteins in GBM and found myeloid cell leukemia-1 (Mcl-1) to be the highest expressed in the majority of malignant gliomas. Mcl-1 was functionally important, as neutralization of Mcl-1 induced apoptosis and increased chemotherapy-induced apoptosis. To determine how Mcl-1 was regulated in glioma, we analyzed the promoter and identified a novel functional single nucleotide polymorphism in an uncharacterized E26 transformation-specific (ETS) binding site. We identified the ETS transcription factor ELK4 as a critical regulator of Mcl-1 in glioma, since ELK4 downregulation was shown to reduce Mcl-1 and increase sensitivity to apoptosis. Importantly the presence of the single nucleotide polymorphism, which ablated ELK4 binding in gliomas, was associated with lower Mcl-1 levels and a greater dependence on Bcl-xL. Furthermore, in vivo, ELK4 downregulation reduced tumor formation in glioblastoma xenograft models. The critical role of ELK4 in Mcl-1 expression and protection from apoptosis in glioma defines ELK4 as a novel potential therapeutic target for GBM.

Involvement of miRNAs in the Differentiation of Human Glioblastoma Multiforme Stem-Like Cells

“…Cluster miR-29a/29b did not induce the expression of the studied differentiation markers, but sensitized the cells to apoptosis by targeting MCL1, a bona-fide target of the miR-29 family [32]. Interestingly, MCL1 is the most over-expressed protein of the BCL2 family in the majority of malignant gliomas, and neutralization of MCL1 in glioma cells has been reported to induce apoptosis and increase chemotherapy-induced apoptosis [38], suggesting that miR-29a/29b over-expression could be studied as a possible therapy for GBM. The up-regulation of cluster miR-221/222 that we observed upon GIC differentiation is more controversial, since this cluster has been found over-expressed in GBM compared to non-transformed tissue [39], being particularly associated to the astrocytic GBM subclass [34].…”

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells

“…Three primary human‐derived (L2b, L3b and Wk1) and one ATCC (U251) GBM neurosphere lines used in this study were obtained from Day et al. (Day et al., 2013, 2011). A commercially available non‐tumourgenic NPCs or ReNcell (Millipore, USA) derived from fetal brain tissue was also included in this study (Donato et al., 2007).…”

Molecular Pathways: Emerging Roles of Mammalian Sirtuin SIRT7 in Cancer

“…SIRT7 deacetylates H3K18Ac at promoters of a network of genes with multiple links to tumor suppression (7). It is directed to a subset of these genes by interacting with the ELK4 transcription factor, which is implicated in prostate and other cancers (16-18). When SIRT7 was inactivated in fibrosarcoma, osteosarcoma, or prostate carcinoma cell lines, H3K18 hyperacetylation led to up-regulation of the tumor suppressive gene network and reversal of important hallmarks of oncogenic transformation, including anchorage independent growth, loss of contact inhibition, and growth factor-independent proliferation.…”