Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors

Abstract

Glioblastoma multiforme (GBM) is a particularly aggressive brain tumor and remains a clinically devastating disease. Despite innovative therapies for the treatment of GBM, there has been no significant increase in patient survival over the past decade. Enzymes that control epigenetic alterations are of considerable interest as targets for cancer therapy because of their critical roles in cellular processes that lead to oncogenesis. Several inhibitors of histone deacetylases (HDACs) have been developed and tested in GBM with moderate success. We found that treatment of GBM cells with HDAC inhibitors caused the accumulation of histone methylation, a modification removed by the lysine specific demethylase 1 (LSD1). This led us to examine the effects of simultaneously inhibiting HDACs and LSD1 as a potential combination therapy. We evaluated induction of apoptosis in GBM cell lines after combined inhibition of LSD1 and HDACs. LSD1 was inhibited by targeted short hairpin RNA or pharmacological means and inhibition of HDACs was achieved by treatment with either vorinostat or PCI-24781. Caspase-dependent apoptosis was significantly increased (>2-fold) in LSD1-knockdown GBM cells treated with HDAC inhibitors. Moreover, pharmacologically inhibiting LSD1 with the monoamine oxidase inhibitor tranylcypromine, in combination with HDAC inhibitors, led to synergistic apoptotic cell death in GBM cells; this did not occur in normal human astrocytes. Taken together, these results indicate that LSD1 and HDACs cooperate to regulate key pathways of cell death in GBM cell lines but not in normal counterparts, and they validate the combined use of LSD1 and HDAC inhibitors as a therapeutic approach for GBM.

Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression

“…Interestingly, previous reports suggest that LSD1 silencing or pharmacologic inhibition exerts antineoplastic effects (12,37). In contrast, our results suggest that LSD1 knockdown induces MYC expression and tumorigenicity.…”

“…There is emerging or renewed interest in targeting the genes implicated in our study [i.e., LSD1 (37,44) and MYC (45,46)] as an anticancer strategy. Notably, these genes, and downstream factors including OLIG2 and SOX2, modulate cellular phenotypes in a dose-dependent manner (47)(48)(49).…”

Doxorubicin enhances Snail/LSD1-mediated PTEN suppression in a PARP1-dependent manner

“…18 Interestingly, according to other recent studies, LSD1 can either render tumor cells resistant to DNA damage or reversely prompt cells to undergo apoptosis in different biological settings, indicating that LSD1 plays a role in cell survival. [23][24][25][26] As mentioned, one of the critical oncogenic roles of Snail lies in apoptosis protection notably through transcriptional repression of PTEN, which serves as a negative regulator of Akt signaling. It would be interesting to find out if LSD1 is involved in Snail-mediated PTEN suppression and cell survival.…”

LSD1/CoREST is an allosteric nanoscale clamp regulated by H3-histone-tail molecular recognition

“…For example, this general, transferable concept is at the basis of the histone deacetylase inhibitors recently introduced for treatment of certain types of lymphomas (1,2). Lysine-specific demethylase-1 (LSD1 or KDM1A) is overexpressed in many solid tumors such as breast, colon, neuroblastoma, bladder, small cell lung, blood, and prostate cancers (3)(4)(5)(6)(7)(8)(9)(10)(11) and plays an important role in leukemia (12), attracting steadily increasing attention as a major target for epigenetic drug discovery (13,14).…”