KRAS inhibition impacts chromatin organization and transcriptional performance in colorectal cancer cells-Reference-Cited by-同舟云学术

KRAS inhibition impacts chromatin organization and transcriptional performance in colorectal cancer cells

Published:2023-12-19 Issue: Volume: Page:
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Author:

Martins Flávia¹,Machado Ana Luísa¹,Ribeiro Andreia¹,Oliveira Susana Mendonça¹,Carvalho Joana¹,Matthiesen Rune²,Velho Sérgia¹

Affiliation:

1. i3S - Health Research and Innovation Institute

2. Universidade Nova de Lisboa

Abstract

Abstract Background Preclinical and clinical data revealed that targeting KRAS mutant tumors is more challenging than expected. While initially sensitive to treatment, cancer cells can rapidly bypass dependence on this oncogene to acquire a drug-tolerant phenotype. Gaining a comprehensive understanding of the mechanisms underlying the transition from a drug-sensitive to a drug-tolerant state is key to obtaining invaluable insights. Such insights will inform the development of therapeutic strategies aimed at disrupting intrinsic or adaptive resistance, ultimately enhancing therapeutic outcomes. Methods Building upon this rationale, we established 3D culture models of mutant-KRAS CRC cell lines with distinct KRAS-dependencies to investigate the response to KRAS silencing. siRNA was used to silence KRAS expression. Cells were grown in 3D, characterized, and analyzed using proteomics. Chromatin states were explored via transmission electron microscopy, and transcriptional performance was assessed through longitudinal RNA-Seq. Results Our approach revealed a unique response in KRAS-dependent cells characterized by G0/G1 cell cycle arrest and entry into a quiescent-like state. Proteomic analysis revealed nucleosome assembly, regulation of gene expression, mRNA splicing, and mRNA processing as the top biological processes that were upregulated in KRAS-dependent CRC cell lines upon KRAS silencing. Additionally, alterations in histone 3 posttranslational modifications and chromatin compaction were also observed, alongside enhanced transcriptional performance, as revealed by longitudinal RNA-Seq analysis. Conclusion Our discoveries substantiate the existence of an epigenetic mechanism responsible for inducing tolerance to KRAS loss. This mechanism involves chromatin reorganization and transcription upregulation, highlighting the remarkable ability of cancer cells to adapt and sustain malignancy without oncogenic KRAS.

Publisher

Research Square Platform LLC

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