Table 3.
The function of histone demethylases in GBM.
| Enzyme | Associated role in GBM | Cell lines/model system used | References |
|---|---|---|---|
| KDM1A | Overexpressed in GBM, particularly in stem-like cells. Constant inhibition decreases proliferation, colony formation, and tumorgenicity, and sensitizes cells to HDAC inhibitors, while transient inhibition increases stem gene expression. Stabilized by GSK3β-mediated phosphorylation, | GSCs, U251, U87, SNB-19, LN-18 | (105–109) |
| KDM2A | Knockdown associated with reduced proliferation, migration, and invasiveness | A172, U251, T98G | (110) |
| KDM2B | Knockdown associated with reductions in cellular viability and self-renewal, increased sensitization to CCNU, and increased susceptibility to TRAIL-induced apoptosis | Patient-derived cultures, U87, T98G | (111, 112) |
| KDM4A | Upregulated in TMZ-resistant GSCs, knockdown results in reduced mTOR pathway activation, reduced invasiveness, and autophagy-dependent apoptosis | A172, U87MG, T98G, U251 | (113–115) |
| KDM4C | Knockdown leads to reduced cellular viability, KDM4C acts as a p53 demethylase to inhibit initiation of apoptotic pathways | GSCs, U87, U251 | (116, 117) |
| KDM5A | Upregulated in TMZ-resistant GSCs, overexpression inhibits TMZ-induced apoptosis in GBM cell lines, inhibition in TMZ-resistant subclones leads to decreased cellular viability | A172, U251, CAS1, DBTRG, U87, GSCs | (113, 118) |
| KDM5B | Higher expression in tumor tissue than surrounding brain, expression inversely correlated with overall survival post-resection | SW1783, U-87, LN-18, Hs683, and T98G | (119) |
| KDM6B | Conflicting evidence: Upregulated in TMZ-resistant GSCs, inhibition has been shown to induce apoptosis in both TMZ-naïve and TMZ-resistant cells. Overexpression has been shown to inhibit neurosphere formation in vitro and in vivo, and STAT3-mediated repression causes normal neurosphere formation | A172, U251, DBTRG, GSCs, NSCs. | (113, 120, 121) |
A summary of the functions of individual histone demethylase enzymes in GBM pathophysiology, and the corresponding model system(s) used and reference to the original publication(s).