SP2509, a Selective Inhibitor of LSD1, Suppresses Retinoblastoma Growth by Downregulating β-catenin Signaling

Jiang, Alan; Wu, Weiqi; Xu, Caixia; Mao, Longbing; Ao, Sha; Guo, Huifeng; Sun, Xiantao; Tao, Jing; Sang, Yi; Huang, Guofu

doi:10.1167/iovs.63.3.20

Cited by 8 publications

(4 citation statements)

References 39 publications

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“…Moreover, we compared the antitumor effects of ZY0511 with SP2509. It is reported that SP2509 blocked the proliferation of Ewing sarcoma, retinoblastoma, and HCC 15,38,39 . Our study demonstrated that ZY0511 exhibited stronger efficiency than SP2509 not only in the IC 50 value and K D against LSD1 but also in IC 50 value against some HCC cells in vitro.…”

Section: Discussionmentioning

confidence: 54%

“…It is reported that SP2509 blocked the proliferation of Ewing sarcoma, retinoblastoma, and HCC. 15,38,39 Our study demonstrated that ZY0511 exhibited stronger efficiency than SP2509 not only in the IC 50 value and K D against LSD1 but also in IC 50 value against some HCC cells in vitro. Collectively, our results suggested that ZY0511 exhibited a stronger anti-HCC effect than SP2509.…”

Section: Discussionmentioning

confidence: 64%

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Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B

Sang

Zhong

Gou

et al. 2023

MedComm

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Lysine‐specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cell‐derived and patient‐derived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damage‐inducible gene 45beta (GADD45B) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B, a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, co‐administration of ZY0511 and DTP3, which specifically enhanced the pro‐apoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 64%

Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B

Sang

Zhong

Gou

et al. 2023

MedComm

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“…The protein from tumor cells and tissues was extracted utilizing RIPA lysis buffer (strong) (K1020, APE×Bio, USA). Subsequently, western blotting was carried out following established procedures [27], using specific antibodies for MCT1 (1:10000, ProteinTech, 20139-1-AP), AMPKα (1:1000, Cell Signaling Technology, #5831), phospho-AMPKα (Thr172) (1:1000, Cell Signaling Technology, #50081), S6 ribosomal protein recombinant antibody (1:5000, ProteinTech, 80208-1-RR), phospho-S6 Ribosomal Protein (Ser240/244) (1:1000, Cell Signaling Technology, #5364), mTOR (1:1000, Cell Signaling Technology, #2983), phospho-mTOR (Ser2481) (1:1000, Cell Signaling Technology, #2974), β-tubulin (1:5000, Protein-Find, HC101-01), and GAPDH (1:10000, ProteinTech, 10494-1-AP). The bound antibodies were subsequently detected by incubating membranes with HRP-conjugated Affinipure Goat Anti-Rabbit IgG(H+L) (1:10000, Protein-Tech, SA00001-2) or HRP-conjugated Affinipure Goat Anti-Mouse IgG(H+L) (1:10000, ProteinTech, SA00001-1) for 1 hour, followed by 3 rounds of 10-minute washing in TBS-0.1% Tween-20.…”

Section: Western Blottingmentioning

confidence: 99%

Deciphering metabolic heterogeneity in retinoblastoma unravels the role of monocarboxylate transporter 1 in tumor progression

Tang,

Liu,

Wang

et al. 2024

Biomark Res

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Background Tumors exhibit metabolic heterogeneity, influencing cancer progression. However, understanding metabolic diversity in retinoblastoma (RB), the primary intraocular malignancy in children, remains limited. Methods The metabolic landscape of RB was constructed based on single-cell transcriptomic sequencing from 11 RB and 5 retina samples. Various analyses were conducted, including assessing overall metabolic activity, metabolic heterogeneity, and the correlation between hypoxia and metabolic pathways. Additionally, the expression pattern of the monocarboxylate transporter (MCT) family in different cell clusters was examined. Validation assays of MCT1 expression and function in RB cell lines were performed. The therapeutic potential of targeting MCT1 was evaluated using an orthotopic xenograft model. A cohort of 47 RB patients was analyzed to evaluate the relationship between MCT1 expression and tumor invasion. Results Distinct metabolic patterns in RB cells, notably increased glycolysis, were identified. This metabolic heterogeneity correlated closely with hypoxia. MCT1 emerged as the primary monocarboxylate transporter in RB cells. Disrupting MCT1 altered cell viability and energy metabolism. In vivo studies using the MCT1 inhibitor AZD3965 effectively suppressed RB tumor growth. Additionally, a correlation between MCT1 expression and optic nerve invasion in RB samples suggested prognostic implications. Conclusions This study enhances our understanding of RB metabolic characteristics at the single-cell level, highlighting the significance of MCT1 in RB pathogenesis. Targeting MCT1 holds promise as a therapeutic strategy for combating RB, with potential prognostic implications.

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“…SP-2509 and OG-L002 exerted anticancer effects apart from their effects on LSD1/LSD2 SP-2509 is a potent and reversible inhibitor of LSD1 [16], which is a novel antitumor target [17]. RNA sequencing expression data from GEPIA2 tumor samples, including pancreatic adenocarcinoma, showed that LSD1 was expressed at higher levels in tumors than normal tissues (Supplementary Fig.…”

Section: Sp-2509 Dramatically Lowered the Viability Of Glycolytically...mentioning

confidence: 99%

Effects of SP-2509 and OG-L002 on lipophagy using target or off-target molecules in glycolysis-suppressed pancreatic ductal adenocarcinoma cells

Aoki,

Zhang,

Aoki

et al. 2023

Preprint

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Although increased aerobic glycolysis is common in cancers, pancreatic ductal adenocarcinoma (PDAC) cells can survive glycolysis suppression. We aimed to identify potential therapeutic targets in glycolysis-suppressed PDAC cells. By screening anticancer metabolic compounds, we identified SP-2509, a selective lysine-specific demethylase (LSD) 1 inhibitor. SP-2509 lowered the viability of three distinct human PDAC cell lines (PANC-1, PK-1, and KLM-1 cells) under glycolysis suppression. The effects of three other LSD1 inhibitors (OG-L002, iadademstat, and T-3775440) on PDAC cell viability were investigated; OG-L002, but not iadademstat or T-3775440, lowered PDAC cell viability under glycolysis suppression, similar to SP-2509. However, knockdown of LSD1/LSD2 failed to lower the viability of PDAC cells subjected to glycolysis suppression. SP-2509 and OG-L002 lowered PDAC cell viability even when given to cells which already been depleted of LSD-1, subjected to glycolysis suppression. Proteomic analyses implied that glucose-starvation causes PDAC cells to switch to mitochondrial oxidative phosphorylation. We observed that fatty acid metabolism is important for the survival of PDAC cells following the suppression of glycolysis. SP-2509 and OG-L002 promoted lipid droplet accumulation in PDAC cells under glycolysis suppression by inhibiting lipophagy. This indicates the significant potential of SP-2509 and OG-L002 to impair oncogenic cell proliferation through regulation of lipophagic fluxes. SP-2509 showed anti-tumor effects of PDAC in 2-DG-treated mice with lipid droplet accumulation and alteration of the tumor microenvironment. Hence, there is potentially new therapeutic strategies for PDAC in the presence of dual inhibition of glycolysis and fatty acids metabolism.

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SP2509, a Selective Inhibitor of LSD1, Suppresses Retinoblastoma Growth by Downregulating β-catenin Signaling

Cited by 8 publications

References 39 publications

Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B

Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B

Deciphering metabolic heterogeneity in retinoblastoma unravels the role of monocarboxylate transporter 1 in tumor progression

Effects of SP-2509 and OG-L002 on lipophagy using target or off-target molecules in glycolysis-suppressed pancreatic ductal adenocarcinoma cells

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