The ELF3 transcription factor is associated with an epithelial phenotype and represses epithelial-mesenchymal transition

Subbalakshmi, Ayalur Raghu; Sahoo, Sarthak; Manjunatha, Prakruthi; Goyal, Shaurya; Kasiviswanathan, Vignesh A; Yeshwanth, M; Ramu, Soundharya; McMullen, Isabelle; Somarelli, Jason A.; Jolly, Mohit Kumar

doi:10.1186/s13036-023-00333-z

Cited by 18 publications

(3 citation statements)

References 108 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sustained epithelial to mesenchymal transition impair regeneration of airway epithelium and enhance expression of pro-inflammatory cytokines [ 42 ]. HOXB2 which promotes polarization [ 43 ] and ELF3, which represses epithelial to mesenchymal transition and participates in bronchial epithelial repair respectively [ 35 , 44 ] together may improve polarization and repair of bronchial epithelium in quercetin-treated COPD patients. This in turn may promote normal differentiation of cells subsequently reducing the expression of TGF-β and IL-8.…”

Section: Discussionmentioning

confidence: 99%

Quercetin improves epithelial regeneration from airway basal cells of COPD patients

McCluskey,

Liu,

Pandey

et al. 2024

Respir Res

View full text Add to dashboard Cite

Background Airway basal cells (BC) from patients with chronic obstructive pulmonary disease (COPD) regenerate abnormal airway epithelium and this was associated with reduced expression of several genes involved in epithelial repair. Quercetin reduces airway epithelial remodeling and inflammation in COPD models, therefore we examined whether quercetin promotes normal epithelial regeneration from COPD BC by altering gene expression. Methods COPD BC treated with DMSO or 1 µM quercetin for three days were cultured at air/liquid interface (ALI) for up to 4 weeks. BC from healthy donors cultured at ALI were used as controls. Polarization of cells was determined at 8 days of ALI. The cell types and IL-8 expression in differentiated cell cultures were quantified by flow cytometry and ELISA respectively. Microarray analysis was conducted on DMSO or 1 µM quercetin-treated COPD BC for 3 days to identify differentially regulated genes (DEG). Bronchial brushings obtained from COPD patients with similar age and disease status treated with either placebo (4 subjects) or 2000 mg/day quercetin (7 subjects) for 6 months were used to confirm the effects of quercetin on gene expression. Results Compared to placebo-, quercetin-treated COPD BC showed significantly increased transepithelial resistance, more ciliated cells, fewer goblet cells, and lower IL-8. Quercetin upregulated genes associated with tissue and epithelial development and differentiation in COPD BC. COPD patients treated with quercetin, but not placebo showed increased expression of two developmental genes HOXB2 and ELF3, which were also increased in quercetin-treated COPD BC with FDR < 0.001. Active smokers showed increased mRNA expression of TGF-β (0.067) and IL-8 (22.0), which was reduced by 3.6 and 4.14 fold respectively after quercetin treatment. Conclusions These results indicate that quercetin may improve airway epithelial regeneration by increasing the expression of genes involved in epithelial development/differentiation in COPD. Trial registration This study was registered at ClinicalTrials.gov on 6-18-2019. The study number is NCT03989271.

show abstract

Section: Discussionmentioning

confidence: 99%

Quercetin improves epithelial regeneration from airway basal cells of COPD patients

McCluskey,

Liu,

Pandey

et al. 2024

Respir Res

View full text Add to dashboard Cite

show abstract

“…Our study found that the ETS family transcription factor ELF3 was upregulated during early response to paclitaxel treatment, and siRNA knockdown of ELF3 was synergistic with paclitaxel treatment at slowing cell line growth. Other studies have found that high ELF3 activity is associated with inhibition of epithelial to mesenchymal transition [ 82 ]. Furthermore, inhibition of ELF3 was found to reduce proliferation across a number of cancer models including lung adenocarcinoma[ 83 ], neuroendocrine carcinoma[ 84 ] and prostate cancer[ 85 ].…”

Section: Discussionmentioning

confidence: 99%

TNBC response to paclitaxel phenocopies interferon response which reveals cell cycle-associated resistance mechanisms

Calistri,

Liby,

et al. 2024

Preprint

View full text Add to dashboard Cite

Paclitaxel is a standard of care neoadjuvant therapy for patients with triple negative breast cancer (TNBC); however, it shows limited benefit for locally advanced or metastatic disease. Here we used a coordinated experimental-computational approach to explore the influence of paclitaxel on the cellular and molecular responses of TNBC cells. We found that escalating doses of paclitaxel resulted in multinucleation, promotion of senescence, and initiation of DNA damage induced apoptosis. Single-cell RNA sequencing (scRNA-seq) of TNBC cells after paclitaxel treatment revealed upregulation of innate immune programs canonically associated with interferon response and downregulation of cell cycle progression programs. Systematic exploration of transcriptional responses to paclitaxel and cancer-associated microenvironmental factors revealed common gene programs induced by paclitaxel, IFNB, and IFNG. Transcription factor (TF) enrichment analysis identified 13 TFs that were both enriched based on activity of downstream targets and also significantly upregulated after paclitaxel treatment. Functional assessment with siRNA knockdown confirmed that the TFs FOSL1, NFE2L2 and ELF3 mediate cellular proliferation and also regulate nuclear structure. We further explored the influence of these TFs on paclitaxel-induced cell cycle behavior via live cell imaging, which revealed altered progression rates through G1, S/G2 and M phases. We found that ELF3 knockdown synergized with paclitaxel treatment to lock cells in a G1 state and prevent cell cycle progression. Analysis of publicly available breast cancer patient data showed that high ELF3 expression was associated with poor prognosis and enrichment programs associated with cell cycle progression. Together these analyses disentangle the diverse aspects of paclitaxel response and identify ELF3 upregulation as a putative biomarker of paclitaxel resistance in TNBC.

show abstract

“…This bidirectional process is a landscape that includes multiple hybrid E–M phenotypes, which possess the properties of both epithelial and mesenchymal cells, thus conferring them with properties like enhanced migration and therapy evasion, which are associated with poor patient prognosis [ 26 ]. Factors like NFATc [ 27 ], SLUG [ 28 ], KLF4 [ 29 ], and ELF3 [ 30 ] have been identified to play crucial roles in regulating EMP.…”

Section: Phenotypic Plasticity Is An Emergent Property Of Cancer Cellsmentioning

confidence: 99%

Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies

Ramisetty,

Subbalakshmi,

Pareek

et al. 2024

JCM

Self Cite

View full text Add to dashboard Cite

Cancer cells, like all other organisms, are adept at switching their phenotype to adjust to the changes in their environment. Thus, phenotypic plasticity is a quantitative trait that confers a fitness advantage to the cancer cell by altering its phenotype to suit environmental circumstances. Until recently, new traits, especially in cancer, were thought to arise due to genetic factors; however, it is now amply evident that such traits could also emerge non-genetically due to phenotypic plasticity. Furthermore, phenotypic plasticity of cancer cells contributes to phenotypic heterogeneity in the population, which is a major impediment in treating the disease. Finally, plasticity also impacts the group behavior of cancer cells, since competition and cooperation among multiple clonal groups within the population and the interactions they have with the tumor microenvironment also contribute to the evolution of drug resistance. Thus, understanding the mechanisms that cancer cells exploit to tailor their phenotypes at a systems level can aid the development of novel cancer therapeutics and treatment strategies. Here, we present our perspective on a team medicine-based approach to gain a deeper understanding of the phenomenon to develop new therapeutic strategies.

show abstract

The ELF3 transcription factor is associated with an epithelial phenotype and represses epithelial-mesenchymal transition

Cited by 18 publications

References 108 publications

Quercetin improves epithelial regeneration from airway basal cells of COPD patients

Quercetin improves epithelial regeneration from airway basal cells of COPD patients

TNBC response to paclitaxel phenocopies interferon response which reveals cell cycle-associated resistance mechanisms

Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies

Contact Info

Product

Resources

About