Catalanotto, M and Vaz, JM and Abshire, C and Youngblood, R and Chu, M and Levine, H and Jolly, MK and Dragoi, A-M (2024) Dual role of CASP8AP2/FLASH in regulating epithelial-to-mesenchymal transition plasticity (EMP). In: Translational Oncology, 39 .
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Abstract
Background: Epithelial-to-mesenchymal transition (EMT) is a developmental program that consists of the loss of epithelial features concomitant with the acquisition of mesenchymal features. Activation of EMT in cancer facilitates the acquisition of aggressive traits and cancer invasion. EMT plasticity (EMP), the dynamic transition between multiple hybrid states in which cancer cells display both epithelial and mesenchymal markers, confers survival advantages for cancer cells in constantly changing environments during metastasis. Methods: RNAseq analysis was performed to assess genome-wide transcriptional changes in cancer cells depleted for histone regulators FLASH, NPAT, and SLBP. Quantitative PCR and Western blot were used for the detection of mRNA and protein levels. Computational analysis was performed on distinct sets of genes to determine the epithelial and mesenchymal score in cancer cells and to correlate FLASH expression with EMT markers in the CCLE collection. Results: We demonstrate that loss of FLASH in cancer cells gives rise to a hybrid E/M phenotype with high epithelial scores even in the presence of TGFβ, as determined by computational methods using expression of predetermined sets of epithelial and mesenchymal genes. Multiple genes involved in cell-cell junction formation are similarly specifically upregulated in FLASH-depleted cells, suggesting that FLASH acts as a repressor of the epithelial phenotype. Further, FLASH expression in cancer lines is inversely correlated with the epithelial score. Nonetheless, subsets of mesenchymal markers were distinctly up-regulated in FLASH, NPAT, or SLBP-depleted cells. Conclusions: The ZEB1low/SNAILhigh/E-cadherinhigh phenotype described in FLASH-depleted cancer cells is driving a hybrid E/M phenotype in which epithelial and mesenchymal markers coexist. © 2023
| Item Type: | Journal Article |
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| Publication: | Translational Oncology |
| Publisher: | Neoplasia Press, Inc. |
| Additional Information: | The copyright for this article belongs to authors. |
| Keywords: | caspase 8; caspase 8 associated protein 2; histone; histone H3; histone H4; transcription factor; transforming growth factor beta; unclassified drug; uvomorulin; vimentin, Article; biogenesis; CADM3 gene; cancer cell; cancer growth; CDH1 gene; cell cycle arrest; cell junction; CGN gene; colony formation; controlled study; differential gene expression; environment; epithelial mesenchymal transition; flow cytometry; gene; gene expression; gene ontology; gene overexpression; gene set enrichment analysis; gene silencing; human; human cell; MARVELD3 gene; mesenchyme; metastasis; microarray analysis; non small cell lung cancer; NPAT gene; pancreas cancer; phenotype; plasticity; protein expression; real time polymerase chain reaction; RNA extraction; RNA sequence; S phase cell cycle checkpoint; scoring system; SLBP gene; tumor growth; Western blotting; ZEB1 gene |
| Department/Centre: | Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering |
| Date Deposited: | 28 Feb 2024 11:26 |
| Last Modified: | 28 Feb 2024 11:26 |
| URI: | https://eprints.iisc.ac.in/id/eprint/83617 |
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