Histone deacetylase inhibitors induce medulloblastoma cell death independent of HDACs recruited in REST repression complexes

Abstract

Background: Repressor element 1-silencing transcription factor (REST) acts as a transcriptional repressor by recruiting several chromatin modifiers, including histone deacetylase (HDAC). Elevated REST expression in medulloblastoma has been associated with tumor progression nevertheless, the tumor shows high sensitivity to HDAC inhibitors (HDACi). However, the functional implications of REST and its requirement for HDACi-induced anti-cancer effects are not well understood.

Methods: In this study, the expression of REST was evaluated across the medulloblastoma subgroups and subtypes using published gene expression data. Further, the expression of REST was modulated using the CRISPR/Cas9 knockout and shRNA knockdown in the Daoy medulloblastoma cell line.

Results: The results of this study showed that the expression of REST is elevated in most medulloblastoma subgroups compared to the non-cancerous cerebellum. Blocking of REST expression resulted in increasing the expression of REST-regulated genes, a moderate decrease in the fraction of the cells in the S-phase, and reducing the cells' migration ability. However, REST deficiency did not lead to a marked decrease in the Daoy cell viability and sensitivity to HDACi.

Conclusion: The findings of this study indicate that REST is not essential for sustaining the proliferation/viability of the Daoy cells. It also revealed that the anti-proliferative effect of HDACi is independent of REST expression.

Keywords: CRISPR/Cas9; HDAC; HDACi; REST; medulloblastoma; shRNA.