Univ. Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France.
INSERM U1132 and USPC Paris-Diderot, Hôpital Lariboisière, Paris, France.
Nucleic Acids Res. 2019 Apr 23;47(7):3407-3421. doi: 10.1093/nar/gkz080.
The proper tissue-specific regulation of gene expression is essential for development and homeostasis in metazoans. However, the illegitimate expression of normally tissue-restricted genes-like testis- or placenta-specific genes-is frequently observed in tumors; this promotes transformation, but also allows immunotherapy. Two important questions are: how is the expression of these genes controlled in healthy cells? And how is this altered in cancer? To address these questions, we used an unbiased approach to test the ability of 350 distinct genetic or epigenetic perturbations to induce the illegitimate expression of over 40 tissue-restricted genes in primary human cells. We find that almost all of these genes are remarkably resistant to reactivation by a single alteration in signaling pathways or chromatin regulation. However, a few genes differ and are more readily activated; one is the placenta-expressed gene ADAM12, which promotes invasion. Using cellular systems, an animal model, and bioinformatics, we find that a non-canonical but druggable TGF-β/KAT2A/TAK1 axis controls ADAM12 induction in normal and cancer cells. More broadly, our data show that illegitimate gene expression in cancer is an heterogeneous phenomenon, with a few genes activatable by simple events, and most genes likely requiring a combination of events to become reactivated.
组织特异性基因表达的正确调控对于后生动物的发育和内稳态至关重要。然而，通常组织受限的基因（如睾丸或胎盘特异性基因）的异常表达在肿瘤中经常观察到；这促进了转化，但也允许免疫治疗。两个重要的问题是：这些基因在健康细胞中的表达是如何控制的？以及在癌症中是如何改变的？为了解决这些问题，我们使用了一种无偏的方法来测试 350 种不同的遗传或表观遗传扰动在原代人细胞中诱导超过 40 种组织受限基因异常表达的能力。我们发现，几乎所有这些基因都对信号通路或染色质调节的单一改变的重新激活具有惊人的抗性。然而，有几个基因有所不同，更容易被激活；一个是胎盘表达的基因 ADAM12，它促进侵袭。我们通过细胞系统、动物模型和生物信息学发现，非经典但可药物治疗的 TGF-β/KAT2A/TAK1 轴控制着正常和癌细胞中 ADAM12 的诱导。更广泛地说，我们的数据表明，癌症中的异常基因表达是一种异质现象，少数基因可以通过简单的事件激活，而大多数基因可能需要多种事件的组合才能重新激活。
