The histone H2A isoform Hist2h2ac is a novel regulator of proliferation and epithelial–mesenchymal transition in mammary epithelial and in breast cancer cells

Monteiro, Fátima Liliana; Vitorino, Rui; Wang, Jun; Cardoso, Hugo Ferrari; Laranjeira, Hugo; Simões, Joana; Caldas, Margarida; Henrique, Rui; Amado, Francisco; Williams, Cecilia; Jerónimo, Carmen; Helguero, Luísa A.

doi:10.1016/j.canlet.2017.03.007

Cited by 25 publications

(22 citation statements)

References 33 publications

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“…Physiologically, H2AFX has been shown to promote the maintenance of genome integrity in male germ cells [15]. In breast cancer, copy number alterations and promoter genetic variations appear to correlate with breast carcinogenesis and the risk of sporadic breast cancer [16]. Accordingly, the genetic variation of the H2AFX promoter has been associated with the risk of glioma, particularly adult glioma [17].…”

Section: Introductionmentioning

confidence: 99%

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Lee

Lin

et al. 2019

Cancers

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Glioblastoma multiforme (GBM) is the most aggressive brain tumor and has a poor prognosis and is poorly sensitive to radiotherapy or temozolomide (TMZ) chemotherapy. Therefore, identifying new biomarkers to predict therapeutic responses of GBM is urgently needed. By using The Cancer Genome Atlas (TCGA) database, we found that the upregulation of histone 2A family member J (H2AFJ), but not other H2AFs, is extensively detected in the therapeutic-insensitive mesenchymal, IDH wildtype, MGMT unmethylated, or non-G-CIMP GBM and is associated with poor TMZ responsiveness independent of radiation. Similar views were also found in GBM cell lines. Whereas H2AFJ knockdown diminished TMZ resistance, H2AFJ overexpression promoted TMZ resistance in a panel of GBM cell lines. Gene set enrichment analysis (GSEA) revealed that H2AFJ upregulation accompanied by the activation of TNF-α/NF-κB and IL-6/STAT3-related pathways is highly predicted. Luciferase-based promoter activity assay further validated that the activities of NF-κB and STAT3 are causally affected by H2AFJ expression in GBM cells. Moreover, we found that therapeutic targeting HADC3 by tacedinaline or NF-κB by ML029 is likely able to overcome the TMZ resistance in GBM cells with H2AFJ upregulation. Significantly, the GBM cohorts harboring a high-level H2AFJ transcript combined with high-level expression of TNF-α/NF-κB geneset, IL-6/STAT3 geneset or HADC3 were associated with a shorter time to tumor repopulation after initial treatment with TMZ. These findings not only provide H2AFJ as a biomarker to predict TMZ therapeutic effectiveness but also suggest a new strategy to combat TMZ-insensitive GBM by targeting the interaction network constructed by TNF-α/NF-κB, IL-6/STAT3, HDAC3, and H2AFJ.

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Section: Introductionmentioning

confidence: 99%

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Lee

Lin

et al. 2019

Cancers

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“…Histone H2A type 2‐c (Hist2h2ac) was expressed in all breast cancers, and its expression was induced by EGF in the CD24 + /CD29hi/DC44hi cell subpopulation. Hist2h2ac silencing inhibited EGF‐induced ZEB1 expression and E‐cadherin downregulation, which suggested that Hist2h2ac is a novel regulator of EMT in breast cancer …”

Section: Small Molecules Against Emtmentioning

confidence: 99%

“…Hist2h2ac silencing inhibited EGF-induced ZEB1 expression and E-cadherin downregulation, which suggested that Hist2h2ac is a novel regulator of EMT in breast cancer. 211 EGF-like repeat and discoidin I-like domain-containing protein 3 (EDIL3) induced EMT and promoted hepatocellular carcinoma migration, invasion, and angiogenesis in vitro. 212 Furthermore, the overexpression of EDIL3…”

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confidence: 99%

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Feng

Chen

Vaziri

et al. 2019

Medicinal Research Reviews

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Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial‐mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc‐finger E‐box‐binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor‐β1, RAC‐α serine/threonine‐protein kinase, Wnt, nuclear factor‐kappa B, peroxisome proliferator‐activated receptor, Notch, and RAS), RNA‐binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.

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“…As observed previously [11], marker gene expression profiles indicated that these stages largely agreed with known keratinocyte states including a BK state (corresponding to stages 1-3), a mitotic state (stage 4), and a DK state (stages 5-7) (Additional file 1: Figure S3). The mitotic state had markedly increased levels of 6 cyclins as well as the histone H2A isoform HIST2H2AC known to be required for proliferation of undifferentiated mammary epithelial cells [15]. Additionally, the mitotic state had high expression of basal markers (KRT5, KRT14) and intermediate expression of early differentiation markers (KRT1, KRT10), suggesting it is a rapidly cycling subpopulation in transition from the BK to DK states (Additional file 1: Figure S3).…”

Section: A Subset Of Keratinocyte-specific Transcription Factors Showmentioning

confidence: 99%

Single-cell transcriptomics reveals spatial and temporal turnover of keratinocyte differentiation regulators

Finnegan

Cho

Luu

et al. 2019

Preprint

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Background: Keratinocyte differentiation requires intricately coordinated spatiotemporal expression changes that specify epidermis structure and function. Results: This paper utilizes single-cell RNA-seq data from 22,338 human foreskin keratinocytes to reconstruct the transcriptional regulation of skin development and homeostasis genes, organizing them by differentiation stage and also into transcription factor (TF)-associated modules. We identify groups of TFs characterized by coordinate expression changes during progression from the undifferentiated basal to the differentiated state and show that these TFs also have concordant differential predicted binding enrichment in the super-enhancers previously reported to turn over between the two states. The identified TFs form a core subset of the regulators controlling gene modules essential for basal and differentiated keratinocyte functions, supporting their nomination as master coordinators of keratinocyte differentiation. Experimental depletion of the TFs ZBED2 and ETV4, both predicted to promote the basal state, induces differentiation. Furthermore, our single-cell RNA expression analysis reveals preferential expression of antioxidant genes in the basal state, suggesting keratinocytes actively suppress reactive oxygen species to maintain the undifferentiated state. Finally, we perform in-silico lineage tracing demonstrating transcriptomic correspondence of basal cell carcinoma (BCC) to a basal keratinocyte subpopulation and squamous cell carcinoma (SCC) to a rapidly proliferating stage that is intermediate between the basal and differentiated cell states, implicating distinct candidate cells of origin for these cancers. Conclusion: Our work demonstrates diverse computational methods integrating single-cell and bulk RNA expression data to advance our understanding of dynamic gene regulation in normal development and in disease.

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The histone H2A isoform Hist2h2ac is a novel regulator of proliferation and epithelial–mesenchymal transition in mammary epithelial and in breast cancer cells

Cited by 25 publications

References 33 publications

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Single-cell transcriptomics reveals spatial and temporal turnover of keratinocyte differentiation regulators

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