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; Sunil Sharma

doi:10.18632/oncotarget.24035

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

Oncotarget. 2018 Jan 6;9(11):9907-9924. doi: 10.18632/oncotarget.24035. eCollection 2018 Feb 9.

Authors

Sumati Gupta¹, Kelly Doyle^{2

3}, Timothy L Mosbruger¹, Andrew Butterfield¹, Alexis Weston¹, Allison Ast^{1

4}, Mohan Kaadige¹, Anupam Verma^{1

4}, Sunil Sharma¹

Affiliations

¹ Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
² Central Laboratory, Intermountain Healthcare, Murray, Utah, USA.
³ Department of Pathology, Primary Children's Hospital, Salt Lake City, Utah, USA.
⁴ Department of Pediatric Hematology/Oncology, Primary Children's Hospital, Salt Lake City, Utah, USA.

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.

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