转分化
恶性肿瘤
表观遗传学
癌症研究
食管癌
生物
医学
内科学
细胞生物学
癌症
基因
遗传学
干细胞
作者
Yongchun Zhang,Dimitris Karagiannis,Helu Liu,Mi Lin,Yinshan Fang,Ming Jiang,Xiao Chen,Supriya Suresh,Haidi Huang,Junjun She,Feiyu Shi,Patrick Yang,Wael El‐Rifai,Alexander Zaika,Anthony E. Oro,Anil K. Rustgi,Timothy C. Wang,Chao Lü,Jianwen Que
标识
DOI:10.1101/2023.09.09.556982
摘要
Abstract 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 squamous versus neuroendocrine lineage in esophageal development and malignancy. Deletion of p63 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). Upregulation 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.
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