PTEN depletion reduces H3K27me3 levels to promote epithelial-to-mesenchymal transition in epithelial colorectal cancer cells

dc.contributor.authorGhobashi, Ahmed H.
dc.contributor.authorKimani, Jane W.
dc.contributor.authorLadaika, Christopher A.
dc.contributor.authorO’Hagan, Heather M.
dc.contributor.departmentMedical and Molecular Genetics, School of Medicine
dc.date.accessioned2024-12-11T13:03:26Z
dc.date.available2024-12-11T13:03:26Z
dc.date.issued2024-11-19
dc.description.abstractEpithelial-to-mesenchymal (EMT) transition is one of the best-known examples of tumor cell plasticity. EMT enhances cancer cell metastasis, which is the main cause of colorectal cancer (CRC)-related mortality. Therefore, understanding underlying molecular mechanisms contributing to the EMT process is crucial to finding druggable targets and more effective therapeutic approaches in CRC. In this study, we demonstrated that phosphatase and tensin homolog (PTEN) knockdown (KD) induces EMT in epithelial CRC, likely through the activation of AKT. PTEN KD modulated chromatin accessibility and reprogrammed gene transcription to mediate EMT in epithelial CRC cells. Active AKT can phosphorylate enhancer of zeste homolog 2 (EZH2) on serine 21, which switches EZH2 from a transcriptional repressor to an activator. Interestingly, PTEN KD reduced the global levels of trimethylation of histone 3 at lysine 27(H3K27me3) in an EZH2-phosphorylation-dependent manner. Additionally, EZH2 phosphorylation at serine 21 reduced the interaction of EZH2 with another polycomb repressive complex 2 (PRC2) component, suppressor of zeste 12 (SUZ12), suggesting that the reduced H3K27me3 levels in PTEN KD cells were due to a disruption of the PRC2 complex. Overall, we demonstrated that PTEN KD modulates changes in gene expression to induce the EMT process in epithelial CRC cells by phosphorylating EZH2 and activates transcription factors such as activator protein 1 (AP1).
dc.eprint.versionFinal published version
dc.identifier.citationGhobashi AH, Kimani JW, Ladaika CA, O'Hagan HM. PTEN depletion reduces H3K27me3 levels to promote epithelial-to-mesenchymal transition in epithelial colorectal cancer cells. PLoS One. 2024;19(11):e0313769. Published 2024 Nov 19. doi:10.1371/journal.pone.0313769
dc.identifier.urihttps://hdl.handle.net/1805/44936
dc.language.isoen_US
dc.publisherPublic Library of Science
dc.relation.isversionof10.1371/journal.pone.0313769
dc.relation.journalPLoS One
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.sourcePMC
dc.subjectColorectal neoplasms
dc.subjectPTEN phosphohydrolase
dc.subjectGene knockdown techniques
dc.subjectPolycomb repressive complex 2
dc.titlePTEN depletion reduces H3K27me3 levels to promote epithelial-to-mesenchymal transition in epithelial colorectal cancer cells
dc.typeArticle
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