The Histone Lysine-specific Demethylase 1 Inhibitor, SP2509 Exerts Cytotoxic Effects against Renal Cancer Cells through Downregulation of Bcl-2 and Mcl-1

Abstract

Lysine-specific histone demethylase 1 (LSD1), also known as KDM1A, can remove the methyl group from lysine 4 and 9 at histone H3, which regulates transcriptional suppression and activation. Recently, high expression of LSD1 in tumors has been shown to be involved in cancer cell proliferation, metastasis, and poor prognosis. We found that SP2509, a potent and reversible inhibitor of LSD1, induced apoptosis in human renal carcinoma (Caki and ACHN) and glioma (U87MG) cells. Pharmacological inhibition and siRNA-mediated silencing of LSD1 expression effectively downregulated anti-apoptotic proteins such as Bcl-2 and Mcl-1. Ectopic expression of these proteins markedly attenuated SP2509-induced apoptosis. At a mechanistic level, we found that inhibition of LSD1 downregulated Bcl-2 at a transcriptional level. Interestingly, protein expression of Mcl-1 was modulated at a post-translation level. Our results reveal that LSD1 could induce apoptotic cell death in renal carcinoma cells through downregulation of Bcl-2 and Mcl-1.

Inhibition of BMI-1 Induces Apoptosis through Downregulation of DUB3-Mediated Mcl-1 Stabilization

“…To detect caspase-3 activity, Caki cells were treated with PTC596 for 24 h, harvested, and incubated with reaction buffer containing substrate [acetyl-Asp-Glu-Val-Asp p-nitroanilide (Ac-DEVD-pNA)] [ 35 ].…”

“…To detect caspase-3 activity, Caki cells were treated with PTC596 for 24 h, harvested, and incubated with reaction buffer containing substrate [acetyl-Asp-Glu-Val-Asp p-nitroanilide (Ac-DEVD-pNA)] [35] RNA was isolated using TRIzol reagent (Life Technologies, Gaithersburg, MD, USA). cDNA was obtained using M-MLV reverse transcriptase (Gibco-BRL, Gaithersburg, MD, USA).…”

Arborinine from Glycosmis parva leaf extract inhibits clear-cell renal cell carcinoma by inhibiting KDM1A/UBE2O signaling

“…The overexpression of KDM1A has been documented in a variety of cancers, and KDM1A inhibitors have, thus, entered clinical trial (23). KDM1A also plays a role in ccRCC, and this effect could be mediated by AR, indicating KDM1A activates downstream gene(s) to exert tumorigenic effect in ccRCC (24)(25)(26)(27). Here, we report that UBE2O is upregulated in the presence of KDM1A in ccRCC (Fig.…”

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

“…We now summarize the information related to MCL-1 as a target and prognostic biomarker in RCC. It was reported that (i) RNAi-mediated silencing of MCL-1 sensitized the Bcl-2 inhibitor ABT-737 to induce apoptosis in RCC cell lines [ 56 ]; (ii) a cell-permeable pyrrazolopyrimidine derivative (compound C) enhances TRAIL-induced apoptosis in human Caki renal cancer cells by reactive oxygen species (ROS)-mediated c-FLIP(L) and MCL-1 downregulation [ 57 ], and (iii) similar results were also found with anisomycin [ 58 ], dicoumarol [ 59 ], curcumin [ 60 ], YM155 [ 61 ] and the histone lysine-specific demethylase 1 inhibitor, SP2509 [ 62 ] in RCC cells. It was also reported that Ras association domain family member 6 (RASSF6) as a tumor suppressor inhibits sorafenib resistance by repressing MCL-1 through the JNK-dependent pathway in RCC cells [ 63 ].…”