Invasive Cell Fate Requires G1 Cell-Cycle Arrest and Histone Deacetylase-Mediated Changes in Gene Expression.
Invasive Cell Fate Requires G1 Cell-Cycle Arrest and Histone Deacetylase-Mediated Changes in Gene Expression.
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DOI：
10.1016/j.devcel.2015.10.002
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发表时间：
2015-10-26
影响因子：
11.8
通讯作者：
Sherwood DR
中科院分区：
文献类型：
--
作者：
Matus DQ;Lohmer LL;Kelley LC;Schindler AJ;Kohrman AQ;Barkoulas M;Zhang W;Chi Q;Sherwood DR
尽管在发育和癌症中发挥着关键作用，但人们对指定侵入性细胞行为的机制知之甚少。通过筛选秀丽隐杆线虫中的转录因子，我们确定G1期细胞周期阻滞是锚细胞（AC）入侵程序的精确调节要求。我们发现，核受体nhr-67/tlx指导AC进入G1期阻滞部分通过调节细胞周期蛋白依赖性激酶抑制剂cki-1。nhr-67的缺失导致非侵入性的有丝分裂AC，其不能表达基质金属蛋白酶或肌动蛋白调节剂，并且缺乏促进侵入的富含侵袭足-F-肌动蛋白的膜突起。我们进一步表明，G1期阻滞是必要的组蛋白去乙酰化酶HDA-1，分化的关键调节剂，以促进促侵袭基因的表达和侵袭伪足的形成。总之，这些结果表明，侵袭性细胞的命运需要G1期阻滞，并且可能需要针对G1期阻滞和活跃循环细胞的策略来阻止转移性癌症。
Despite critical roles in development and cancer, the mechanisms that specify invasive cellular behavior are poorly understood. Through a screen of transcription factors in Caenorhabditis elegans, we identified G1 cell-cycle arrest as a precisely regulated requirement of the anchor cell (AC) invasion program. We show that the nuclear receptor nhr-67/tlx directs the AC into G1 arrest in part through regulation of the cyclin-dependent kinase inhibitor cki-1. Loss of nhr-67 resulted in non-invasive, mitotic ACs that failed to express matrix metalloproteinases or actin regulators and lack invadopodia—F-actin rich membrane protrusions that facilitate invasion. We further show that G1 arrest is necessary for the histone deacetylase HDA-1, a key regulator of differentiation, to promote pro-invasive gene expression and invadopodia formation. Together these results suggest that invasive cell fate requires G1 arrest and that strategies targeting both G1 arrested and actively cycling cells may be needed to halt metastatic cancer.