Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan.
Department of Experimental Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan.
Biochem Biophys Res Commun. 2020 Feb 19;522(4):897-902. doi: 10.1016/j.bbrc.2019.11.145. Epub 2019 Dec 3.
Induction of cellular senescence in cancerous cells is an important strategy which is used in the treatment of cancer. However, cancer cells are capable of exhibiting resistance to cellular senescence through inactivation of tumor suppressors. Because of this, establishment of a route to cellular senescence induction in cancer cells is a crucial direction for developing future cancer therapies. In this study, we demonstrate the involvement of TSC-22 homologous gene-1 (THG-1, also called TSC22D4) in the suppression of cellular senescence. CRISPR/Cas9 gene editing was used to establish THG-1 knockout (KO) cells in a THG-1 positive esophageal tumor cell line. It was found that THG-1 KO cells exhibited delayed cell proliferation as well as cellular senescence. The elevated expression of the CDK inhibitor P21(CDKN1A) was also identified in senescent cells. Through the investigation of the upstream pathway for induction of P21(CDKN1A), the JUNB pathway was identified to play a critical role in P21(CDKN1A) transcription; in fact, the siRNA-mediated knockdown of JUNB reduced the abundance of P21(CDKN1A) mRNA and cellular senescence in THG-1 KO cells. These findings provide a novel insight into the induction of cellular senescence in THG-1 positive cancer cells.
诱导癌细胞衰老被认为是癌症治疗的重要策略。然而，癌细胞可以通过失活肿瘤抑制因子来抵抗细胞衰老。因此，建立诱导癌细胞衰老的途径是开发未来癌症治疗方法的关键方向。在本研究中，我们证明了 TSC-22 同源基因-1（THG-1，也称为 TSC22D4）在抑制细胞衰老中的作用。我们使用 CRISPR/Cas9 基因编辑技术在 THG-1 阳性食管癌细胞系中建立了 THG-1 敲除（KO）细胞。结果发现，THG-1 KO 细胞的增殖和细胞衰老明显延迟。衰老细胞中 CDK 抑制剂 P21(CDKN1A)的表达也明显升高。通过对 P21(CDKN1A)诱导的上游通路的研究，我们发现 JUNB 通路在 P21(CDKN1A)转录中起关键作用；事实上，siRNA 介导的 JUNB 敲低减少了 THG-1 KO 细胞中 P21(CDKN1A)mRNA 的丰度和细胞衰老。这些发现为 THG-1 阳性癌细胞中细胞衰老的诱导提供了新的见解。
