Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression

Abstract

Glioblastoma (GBM) is comprised of distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation. Here, ZBTB18 is primarily silenced in the mesenchymal subtype of GBM through aberrant promoter methylation. Loss of ZBTB18 contributes to the aggressive phenotype of glioblastoma through regulation of poor prognosis-associated signatures. Restitution of ZBTB18 expression reverses the phenotype and impairs tumor-forming ability. These results indicate that ZBTB18 functions as a tumor suppressor in GBM through the regulation of genes associated with phenotypically aggressive properties. Implications This study characterizes the role of the putative tumor suppressor ZBTB18 and its regulation by promoter hypermethylation, which appears to be a common mechanism to silence ZBTB18 in the mesenchymal subtype of GBM and provides a new mechanistic opportunity to specifically target this tumor subclass.

ZBTB18 inhibits SREBP-dependent fatty acid synthesis by counteracting CTBPs and KDM1A/LSD1 activity in glioblastoma

“…S3A). This is consistent with our reported 8 role of ZBTB18 as inhibitor of mesenchymal signatures in GBM and with previous studies indicating that CTBP2 promotes tumorigenesis and EMT (27,34).…”

“…Consistent with our previous study (27), ZBTB18 affected cell proliferation, apoptosis and migration. ZBTB18 LDL mutant (ZBTB18-mut) also appeared to have a mild effect on apoptosis and proliferation while migration was not impaired ( Supplementary Fig.…”

“…Lentiviral stocks and cell infection were performed as previously described (27). Ectopic protein expression was determined by immunoblotting with an anti-Flag M2 antibody (Sigma).…”

“…For CTBP2 knockdown, CTBP2 short hairpin cloned in the pLKO lentiviral vector was used (Sigma, #TRCN0000013745). Lentiviral particles were generated in HEK293T cells as previously described (27). Selection of infected cells was conducted with 2 μg/ml of Puromycin (Sigma).…”

“…Previously, we have identified ZBTB18 as tumor suppressor in GBM which functions as a transcriptional repressor of mesenchymal genes and impairs tumor formation (26,27).…”