Sharma, S and Rani, H and Mahesh, Y and Jolly, MK and Dixit, J and Mahadevan, V (2024) Loss of p53 epigenetically modulates epithelial to mesenchymal transition in colorectal cancer. In: Translational Oncology, 43 .
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Abstract
Epithelial to Mesenchymal transition (EMT) drives cancer metastasis and is governed by genetic and epigenetic alterations at multiple levels of regulation. It is well established that loss/mutation of p53 confers oncogenic function to cancer cells and promotes metastasis. Though transcription factors like ZEB1, SLUG, SNAIL and TWIST have been implied in EMT signalling, p53 mediated alterations in the epigenetic machinery accompanying EMT are not clearly understood. This work attempts to explore epigenetic signalling during EMT in colorectal cancer (CRC) cells with varying status of p53. Towards this, we have induced EMT using TGFβ on CRC cell lines with wild type, null and mutant p53 and have assayed epigenetic alterations after EMT induction. Transcriptomic profiling of the four CRC cell lines revealed that the loss of p53 confers more mesenchymal phenotype with EMT induction than its mutant counterparts. This was also accompanied by upregulation of epigenetic writer and eraser machinery suggesting an epigenetic signalling cascade triggered by TGFβ signalling in CRC. Significant agonist and antagonistic relationships observed between EMT factor SNAI1 and SNAI2 with epigenetic enzymes KDM6A/6B and the chromatin organiser SATB1 in p53 null CRC cells suggest a crosstalk between epigenetic and EMT factors. The observed epigenetic regulation of EMT factor SNAI1 correlates with poor clinical outcomes in 270 colorectal cancer patients taken from TCGA-COAD. This unique p53 dependent interplay between epigenetic enzymes and EMT factors in CRC cells may be exploited for development of synergistic therapies for CRC patients presenting to the clinic with loss of p53. © 2023 The Authors
| Item Type: | Journal Article |
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| Publication: | Translational Oncology |
| Publisher: | Neoplasia Press, Inc. |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | alpha1 integrin; cadherin; chromobox protein homolog 5; emt inducing transcription factor; protein p53; transcription factor; transcription factor Sox2; transforming growth factor beta; unclassified drug; vimentin, Akt/mTOR signaling; Article; Bradford assay; cancer epigenetics; carcinogenesis; cell migration; clinical outcome; colorectal cancer; colorectal cancer cell line; controlled study; correlation analysis; cross linking; differential expression analysis; DNA fragmentation; DNA repair; downstream processing; EGFR signaling; electrochemiluminescence; epigenetics; epithelial mesenchymal transition; false discovery rate; flow cytometry; gene expression; gene expression profiling; gene set enrichment analysis; HCT 116 cell line; hippo signaling; HT-29 cell line; human; human cell; human tissue; illumina sequencing; immunoblotting; kinetics; MAPK signaling; metastasis; molecular interaction; NF kB signaling; pancreatic ductal carcinoma; phenotype; polyacrylamide gel electrophoresis; protein expression level; quality control; real time reverse transcription polymerase chain reaction; RNA extraction; RNA sequencing; survival analysis; transcriptome sequencing; transwell assay; tumor microenvironment; upregulation; validation process; Western blotting; wound healing assay |
| Department/Centre: | Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering |
| Date Deposited: | 23 Apr 2024 10:25 |
| Last Modified: | 23 Apr 2024 10:25 |
| URI: | https://eprints.iisc.ac.in/id/eprint/84614 |
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