Pharmacological inhibition of LSD1 activity blocks REST-dependent medulloblastoma cell migration

Cell Communication and Signaling : CCS
Keri CallegariVidya Gopalakrishnan

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children. Current problems in the clinic include metastasis, recurrence, and treatment-related sequelae that highlight the need for targeted therapies. Epigenetic perturbations are an established hallmark of human MB and expression of Lysine Specific Demethylase 1 (LSD1) is elevated in MBs compared to normal tissue, suggesting that LSD1 inhibitors may have efficacy against human MB tumors. Expression of LSD1 was examined across a publicly-available database and correlated with patient outcomes. Sonic Hedgehog (SHH) MB samples were clustered based on expression of LSD1 and LSD1-associated RE-1 silencing transcription factor (REST) target genes as well as genes involved in metastasis. Resulting clusters were examined for patient outcomes associated with LSD1 and REST expression. Human SHH MB cell lines were transduced with a REST-transgene to create isogenic cell pairs. In vitro viability and cell migration assays were used to examine the effect of LSD1 knockdown or inhibition on these parameters. We demonstrate that subsets of SHH MB tumors have elevated LSD1 expression coincident with increased expression of its deubiquitylase, USP7, and REST. Patients with co-ele...Continue Reading

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Citations

May 23, 2019·Frontiers in Pharmacology·Zhiru WangYichao Zheng
Aug 21, 2020·Journal of Neuro-oncology·Amanda R HaltomSoumen Khatua
Jan 8, 2020·International Journal of Molecular Sciences·Jose M Garcia-ManteigaJacopo Meldolesi
Jan 21, 2021·Molecular Oncology·Shavali ShaikVidya Gopalakrishnan
Aug 25, 2020·Acta Pharmaceutica Sinica. B·Yuan FangBin Yu
Nov 7, 2020·Drug Discovery Today·Lauraine NininahazweZhe-Sheng Chen
Feb 21, 2021·Molecular Cancer Research : MCR·Min LiWangming Zhang
Jun 3, 2021·International Journal of Molecular Sciences·Agata StrejczekAnna-Maria Barciszewska
Jun 8, 2021·Frontiers in Oncology·Yalin LuQiang Huang
Oct 5, 2021·Expert Opinion on Therapeutic Targets·Shavali ShaikVidya Gopalakrishnan

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Datasets Mentioned

BETA
GSE85217
GSE109401
GSE37418

Methods Mentioned

BETA
light microscopy
RNA-Seq

Software Mentioned

ArrayTrack
GraphPad Prism
Ingenuity
CellCounter
GeneDiff
IPA
GraphPad
LightCycler

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