CBX2 Shapes Chromatin Accessibility Promoting AML Via P38 MAPK Signaling Pathway

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2022 Jun 10

PMID 35681235

Authors

Nunzio Del Gaudio

Antonella Di Costanzo

Ning Qing Liu

Lidio Conte

Carmela DellAversana

Guglielmo Bove

Rosaria Benedetti

Liliana Montella

Fortunato Ciardiello

Vincenzo Carafa

Concetta Ambrosino

Valeria Tucci

Mariarosaria Conte

Joost H A Martens

Hendrik G Stunnenberg

Angela Nebbioso

Lucia Altucci

Affiliations

Soon will be listed here.

Abstract

Background: The dynamic epigenome and proteins specialized in the interpretation of epigenetic marks critically contribute to leukemic pathogenesis but also offer alternative therapeutic avenues. Targeting newly discovered chromatin readers involved in leukemogenesis may thus provide new anticancer strategies. Accumulating evidence suggests that the PRC1 complex member CBX2 is overexpressed in solid tumors and promotes cancer cell survival. However, its role in leukemia is still unclear.

Methods: We exploited reverse genetic approaches to investigate the role of CBX2 in human leukemic cell lines and ex vivo samples. We also analyzed phenotypic effects following CBX2 silencing using cellular and molecular assays and related functional mechanisms by ATAC-seq and RNA-seq. We then performed bioinformatic analysis of ChIP-seq data to explore the influence of histone modifications in CBX2-mediated open chromatin sites. Lastly, we used molecular assays to determine the contribution of CBX2-regulated pathways to leukemic phenotype.

Results: We found CBX2 overexpressed in leukemia both in vitro and ex vivo samples compared to CD34 cells. Decreased CBX2 RNA levels prompted a robust reduction in cell proliferation and induction of apoptosis. Similarly, sensitivity to CBX2 silencing was observed in primary acute myeloid leukemia samples. CBX2 suppression increased genome-wide chromatin accessibility followed by alteration of leukemic cell transcriptional programs, resulting in enrichment of cell death pathways and downregulation of survival genes. Intriguingly, CBX2 silencing induced epigenetic reprogramming at p38 MAPK-associated regulatory sites with consequent deregulation of gene expression.

Conclusions: Our results identify CBX2 as a crucial player in leukemia progression and highlight a potential druggable CBX2-p38 MAPK network in AML.

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