Oncotarget

Research Papers:

Reversible LSD1 inhibition with HCI-2509 induces the p53 gene expression signature and disrupts the MYCN signature in high-risk neuroblastoma cells

Sumati Gupta _, Kelly Doyle, Timothy L. Mosbruger, Andrew Butterfield, Alexis Weston, Allison Ast, Mohan Kaadige, Anupam Verma and Sunil Sharma

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Oncotarget. 2018; 9:9907-9924. https://doi.org/10.18632/oncotarget.24035

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Abstract

Sumati Gupta1, Kelly Doyle2,3, Timothy L. Mosbruger1, Andrew Butterfield1, Alexis Weston1, Allison Ast1,4, Mohan Kaadige1, Anupam Verma1,4 and Sunil Sharma1

1Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA

2Central Laboratory, Intermountain Healthcare, Murray, Utah, USA

3Department of Pathology, Primary Children’s Hospital, Salt Lake City, Utah, USA

4Department of Pediatric Hematology/Oncology, Primary Children’s Hospital, Salt Lake City, Utah, USA

Correspondence to:

Sumati Gupta, email: [email protected]

Keywords: neuroblastoma; MYCN; LSD1; HCI-2509; p53

Received: June 02, 2017     Accepted: November 20, 2017     Published: January 06, 2018

ABSTRACT

Lysine-Specific Demethylase 1 (LSD1) over-expression correlates with poorly differentiated neuroblastoma and predicts poor outcome despite multimodal therapy. We have studied the efficacy of reversible and specific LSD1 inhibition with HCI-2509 in neuroblastoma cell lines and particularly the effect of HCI-2509 on the transcriptomic profile in MYCN amplified NGP cells. Cell survival assays show that HCI-2509 is cytotoxic to poorly differentiated neuroblastoma cell lines in low micromole or lower doses. Transcriptional profiling of NGP cells treated with HCI-2509 shows a significant effect on p53, cell cycle, MYCN and hypoxia pathway gene sets. HCI-2509 results in increased histone methyl marks and p53 levels along with cell cycle arrest in the G2/M phase and inhibition of colony formation of NGP cells. Our findings indicate that LSD1 inhibition with HCI-2509 has a multi-target effect in neuroblastoma cell lines, mediated in part via p53. MYCN-amplified neuroblastoma cells have a targeted benefit as HCI-2509 downregulates the MYCN upregulated gene set.


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