Epigenetic regulation of p63 blocks squamous-to-neuroendocrine transdifferentiation in esophageal development and malignancy
While cell fate determination and maintenance are important in establishing and preserving tissue identity and function during development, aberrant cell fate transition leads to cancer cell heterogeneity and resistance to treatment. Here, we report an unexpected role for the transcription factor p63 (Trp63/TP63) in the fate choice of the squamous versus neuroendocrine lineage in esophageal development and malignancy. Deletion of <i>p63</i> results in extensive neuroendocrine differentiation in the developing mouse esophagus and esophageal progenitors derived from human embryonic stem cells. In human esophageal neuroendocrine carcinoma (eNEC) cells, p63 is transcriptionally silenced by EZH2-mediated H3K27 trimethylation (H3K27me3). Up-regulation of the major p63 isoform ΔNp63α, through either ectopic expression or EZH2 inhibition, promotes squamous transdifferentiation of eNEC cells. Together, these findings uncover p63 as a rheostat in coordinating the transition between squamous and neuroendocrine cell fates during esophageal development and tumor progression.
Authors
- Wael El‐Rifai (ORCID: https://orcid.org/0000-0003-2101-6098)
- Kuancan Liu (ORCID: https://orcid.org/0000-0002-2470-7479)
- Ming Jiang (ORCID: https://orcid.org/0000-0002-1999-1866)
- Yinshan Fang (ORCID: https://orcid.org/0000-0001-9249-4498)
- Anil K. Rustgi (ORCID: https://orcid.org/0000-0002-6439-6919)
- Junjun She (ORCID: https://orcid.org/0000-0001-5104-663X)
- Anthony E. Oro (ORCID: https://orcid.org/0000-0002-6261-138X)
- Alexander Zaika (ORCID: https://orcid.org/0000-0001-6760-2020)
- Feiyu Shi (ORCID: https://orcid.org/0000-0001-5691-1362)
- Jiangying Liu
- J. Carlos Angel (ORCID: https://orcid.org/0000-0001-6531-7381)
- Xiao Chen (ORCID: https://orcid.org/0000-0001-5059-8846)
- Jianwen Que (ORCID: https://orcid.org/0000-0002-6540-6701)
- Chao Lü (ORCID: https://orcid.org/0000-0003-0982-8122)
- Helu Liu (ORCID: https://orcid.org/0000-0002-4527-4115)
- Dimitris Karagiannis (ORCID: https://orcid.org/0000-0002-4394-1076)
- Mi Lin (ORCID: https://orcid.org/0000-0001-9357-8642)
- Timothy C. Wang
- Dan Luo (ORCID: https://orcid.org/0000-0003-2628-8391)
- Yongchun Zhang (ORCID: https://orcid.org/0009-0009-9949-0604)
- Supriya Suresh (ORCID: https://orcid.org/0000-0002-3907-0984)
- Patrick Yang
- Haidi Huang
- Guang‐Tan Lin
Institutions
- Fujian Medical University (CN)
- Westchester Medical Center (US)
- Shanghai Jiao Tong University (CN)
- Xiamen University (CN)
- Columbia University Irving Medical Center (US)
- Zhejiang Hospital (CN)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Union Hospital (US)
- Institute of Deep-Sea Science and Engineering (CN)
- Sylvester Comprehensive Cancer Center (US)
- Second Affiliated Hospital of Zhejiang University (CN)
- Union Hospital (CN)
- Miami VA Healthcare System (US)
- Zhejiang University (CN)
- Columbia University (US)
- Stanford University (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-10-09
- DOI
- https://doi.org/10.1126/sciadv.adq0479
- Citations
- 9
- Primary Topic
- Neuroendocrine Tumor Research Advances
- Type
- article
- Field-Weighted Citation Impact
- 3.48