SETDB1 fuels the lung cancer phenotype by modulating epigenome, 3D genome organization and chromatin mechanical properties

Abstract

Imbalance in the finely orchestrated system of chromatin-modifying enzymes is a hallmark of many pathologies such as cancers, since causing the affection of the epigenome and transcriptional reprogramming. Here, we demonstrate that a loss-of-function mutation (LOF) of the major histone lysine methyltransferase SETDB1 possessing oncogenic activity in lung cancer cells leads to broad changes in the overall architecture and mechanical properties of the nucleus through genome-wide redistribution of heterochromatin, which perturbs chromatin spatial compartmentalization. Together with the enforced activation of the epithelial expression program, cytoskeleton remodeling, reduced proliferation rate and restricted cellular migration, this leads to the reversed oncogenic potential of lung adenocarcinoma cells. These results emphasize an essential role of chromatin architecture in the determination of oncogenic programs and illustrate a relationship between gene expression, epigenome, 3D genome and nuclear mechanics.

XBP1 impacts lung adenocarcinoma progression by promoting plasma cell adaptation to the tumor microenvironment

“…This implies that the B cell infiltration in LUAD may be associated with the NK cell population as well. Moreover, new research shows that SETDB1 fuels the phenotype of lung cancer by modulating the epigenome and resists anti-CTLA4 and anti-PD1 combination therapy ( Griffin et al, 2021 ; Zakharova et al, 2022 ). Pasquarella et al (2016) also detected an increased level of Xbp1 expression in SETDB1-deficient B cells.…”

Multilevel view on chromatin architecture alterations in cancer

“…For example, SETDB1 is a histone H3K9 methyltransferase, which is often up-regulated in different types of tumors (Lazaro-Camp et al, 2021). In lung cancer cells, the inactivation of the SETDB1 gene leads to recovery features of a normal epithelial phenotype, including an increase in spatial cis-contacts within the B-compartment and a decrease in inter-compartment interactions (Zakharova et al, 2022).…”

3D genomic organization in cancers

“…Loop is a fundamental spatial regulatory structure that generally occurs between enhancers and promoters within TADs, which is necessary for gene expression [23]. Existing study has demonstrated the important regulatory role of 3D chromatin structure in gene expression [24]. It is reported that perturbations of 3D genome organization caused by the loss of H3K9 methylation activity will affect the gene expression patterns [25].…”

“…Existing study has demonstrated the important regulatory role of 3D chromatin structure in gene expression [24]. It is reported that perturbations of 3D genome organization caused by the loss of H3K9 methylation activity will affect the gene expression patterns [25]. The interaction network between super enhancers (SE) and super silencers, as well as key transcription factors (TFs) also can regulate gene expression [26].…”