The association between bromodomain proteins and cancer stemness in different solid tumor types

Abstract

Cancer stemness, which covers the stem cell-like molecular traits of cancer cells, is essential for tumor development, progression and relapse. Both transcriptional and epigenetic aberrations are essentially connected with cancer stemness. The engagement of bromodomain (BrD) proteins-a family of epigenetic factors-has been presented in the pathogenesis of several tumor types, although their association with cancer stemness remains largely unknown. Here, we harnessed TCGA and GEO databases and used several bioinformatic tools (ie, Oncomine, PrognoScan, GEPIA2, TIMER2.0, TISIDB, GSEA, R2 platform) to characterize the association between the BrD family members' expression and cancer stemness in solid tumors. Our results demonstrate that significant upregulation of ATAD2 and SMARCA4, and downregulation of SMARCA2 is consistently associated with enriched cancer stem cell-like phenotype, respectively. Especially, higher-grade tumors that display stem cell-like properties overexpress ATAD2. In contrast to most BrD members, the gene expression profiles of ATAD2 HIGH expressing tumors are strongly enriched with known markers of stem cells and with specific targets for c-Myc transcription factor.For other BrD proteins, the association with cancer de-differentiation status is rather tumor-specific. Our results demonstrate for the first time the relation between distinct BrD family proteins and cancer stemness across 27 solid tumor types. Specifically, our approach allowed us to discover a robust association of high ATAD2 expression with cancer stemness and reveal its' versatility in tumors.

Identification of bromodomain-containing proteins prognostic value and expression significance based on a genomic landscape analysis of ovarian serous cystadenocarcinoma

“…Furthermore, Patrycja et al. found a significant correlation between distinct BRDs and stemness maintenance in 27 solid cancer types ( 81 ). Hao and his colleagues found that EP300 could induce an increase in ALKBH5 expression to reduce the m6A level of FOXM1 mRNA by upregulating H3K27ac, resulting in enhanced FOXM1 mRNA levels and EMT cascade activation in melanoma ( 82 ).…”

Bromodomain (BrD) Family Members as Regulators of Cancer Stemness—A Comprehensive Review

“…On the other hand, in pancreatic cancer, the upregulation of SMARCA2 associates with disease progression, being significantly positively correlated with patients’ poor survival, larger tumor size, metastases, lymphatic invasion, and stage IV disease [ 131 ]. We have recently reported a consistent negative association of SMARCA2 expression with cancer de-differentiation status [ 118 ]. However, the molecular studies demonstrating the precise role of SMARCA2 in the regulation of cancer stemness across distinct types of solid tumors are insufficient to make an unequivocal decision on whether SMARCA2 is a negative cancer stemness regulator.…”

“…Recently, we have demonstrated that SMARCA4 exhibit a consistent positive correlation with cancer stemness (assessed based on transcriptomic features of TCGA cancers). At the same time, SMARCA2—shows a negative association with tumor de-differentiation status, regardless of the tumor type [ 118 ]. Indeed, the fundamental role of SMARCA4 in the regulation of cancer stemness was previously reported by Yoshikawa et al [ 119 , 120 ] in colorectal cancers.…”

“…Recently, Hagiwara et al [ 153 ] have demonstrated that an oncogenic protein, MUC1-C, that drives lineage plasticity in prostate cancer progression also integrates the activation of PBRM1 with the regulation of redox balance, pluripotency markers’ expression, and cancer stem cell-like state in pancreatic cancer. Our previous report demonstrated a negative association of PBRM1 expression with cancer stemness in several types of solid tumors, including kidney and pancreatic cancers, although mechanistic studies are missing [ 118 ].…”

“…Molecularly, BAZ1B activates both PI3K/Akt and IL-6/STAT3 oncogenic signaling pathways, which were previously linked to cancer stemness [ 167 ]. In our previous report, we determined a positive correlation between BAZ1B expression and cancer stemness in several types of solid tumors, including breast and lung cancers [ 118 ]. Therefore, BAZ1B might be concerned as a cancer stemness-promoting factor.…”