Institut Curie, PSL Research University, CNRS, Sorbonne Université, Nuclear Dynamics Unit, Equipe Labellisée Ligue contre le Cancer, Paris, France.
Institut Curie, PSL Research University, Centre de Recherche, Sorbonne Université, Cell Biology and Cancer Unit, Paris, France.
Commun Biol. 2021 Mar 26;4(1):417. doi: 10.1038/s42003-021-01941-5.
Tumour evolution is driven by both genetic and epigenetic changes. CENP-A, the centromeric histone H3 variant, is an epigenetic mark that directly perturbs genetic stability and chromatin when overexpressed. Although CENP-A overexpression is a common feature of many cancers, how this impacts cell fate and response to therapy remains unclear. Here, we established a tunable system of inducible and reversible CENP-A overexpression combined with a switch in p53 status in human cell lines. Through clonogenic survival assays, single-cell RNA-sequencing and cell trajectory analysis, we uncover the tumour suppressor p53 as a key determinant of how CENP-A impacts cell state, cell identity and therapeutic response. If p53 is functional, CENP-A overexpression promotes senescence and radiosensitivity. Surprisingly, when we inactivate p53, CENP-A overexpression instead promotes epithelial-mesenchymal transition, an essential process in mammalian development but also a precursor for tumour cell invasion and metastasis. Thus, we uncover an unanticipated function of CENP-A overexpression to promote cell fate reprogramming, with important implications for development and tumour evolution.
肿瘤的进化是由遗传和表观遗传变化共同驱动的。着丝粒组蛋白 H3 变体 CENP-A 是一种表观遗传标记，当过度表达时，它会直接干扰遗传稳定性和染色质。虽然 CENP-A 过表达是许多癌症的共同特征，但它如何影响细胞命运和对治疗的反应尚不清楚。在这里，我们建立了一个可诱导和可逆的 CENP-A 过表达的可调系统，结合人细胞系中 p53 状态的转换。通过集落形成存活测定、单细胞 RNA 测序和细胞轨迹分析，我们发现肿瘤抑制因子 p53 是 CENP-A 如何影响细胞状态、细胞身份和治疗反应的关键决定因素。如果 p53 是功能性的，CENP-A 过表达会促进衰老和放射敏感性。令人惊讶的是，当我们失活 p53 时，CENP-A 过表达反而会促进上皮-间充质转化，这是哺乳动物发育过程中的一个重要过程，但也是肿瘤细胞侵袭和转移的前体。因此，我们揭示了 CENP-A 过表达促进细胞命运重编程的意外功能，这对发育和肿瘤进化具有重要意义。
