Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Case Western Reserve University-MetroHealth Medical Research Center, Cleveland, OH, USA.
Cell Death Dis. 2019 Jul 15;10(8):539. doi: 10.1038/s41419-019-1774-z.
In cancer, cellular senescence is a complex process that leads to inhibition of proliferation of cells that may develop a neoplastic phenotype. A plethora of signaling pathways, when dysregulated, have been shown to elicit a senescence response. Two well-known tumor suppressor pathways, controlled by the p53 and retinoblastoma proteins, have been implicated in maintaining the cellular senescence phenotype. Kindlin-2, a member of an actin cytoskeleton organizing and integrin activator proteins, has been shown to play a key role in the regulation of several hallmarks of several cancers, including breast cancer (BC). The molecular mechanisms whereby Kindlin-2 regulates cellular senescence in BC tumors remains largely unknown. Here we show that Kindlin-2 regulates cellular senescence in part through its interaction with p53, whereby it regulates the expression of the p53-responsive genes; i.e., SerpinB2 and p21, during the induction of senescence. Our data show that knockout of Kindlin-2 via CRISPR/Cas9 in several BC cell lines significantly increases expression levels of both SerpinB2 and p21 resulting in the activation of hallmarks of cellular senescence. Mechanistically, interaction between Kindlin-2 and p53 at the promotor level is critical for the regulated expression of SerpinB2 and p21. These findings identify a previously unknown Kindlin-2/p53/SerpinB2 signaling axis that regulates cellular senescence and intervention in this axis may serve as a new therapeutic window for BCs treatment.
在癌症中，细胞衰老（cellular senescence）是一个复杂的过程，它会导致可能发展出肿瘤表型的细胞增殖受到抑制。大量失调的信号通路已被证明会引发衰老反应。两种众所周知的肿瘤抑制因子通路，由 p53 和视网膜母细胞瘤蛋白（retinoblastoma protein）控制，已被认为在维持细胞衰老表型方面发挥作用。Kindlin-2 是肌动蛋白细胞骨架组织和整合素激活蛋白的成员之一，它被证明在调节包括乳腺癌（breast cancer，BC）在内的多种癌症的几个标志性特征方面发挥着关键作用。Kindlin-2 调节 BC 肿瘤细胞衰老的分子机制在很大程度上仍然未知。在这里，我们表明 Kindlin-2 通过与 p53 相互作用部分调节细胞衰老，通过这种相互作用，它调节了衰老诱导过程中 p53 反应基因 SerpinB2 和 p21 的表达。我们的数据表明，通过 CRISPR/Cas9 在几种 BC 细胞系中敲除 Kindlin-2 会显著增加 SerpinB2 和 p21 的表达水平，从而激活细胞衰老的标志性特征。从机制上讲，Kindlin-2 和 p53 在启动子水平上的相互作用对于 SerpinB2 和 p21 的调节表达至关重要。这些发现确定了一个以前未知的 Kindlin-2/p53/SerpinB2 信号轴，它调节细胞衰老，干预这个轴可能成为治疗 BC 的新治疗窗口。
