Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo 113-0033, Japan.
Genes (Basel). 2021 Apr 8;12(4):539. doi: 10.3390/genes12040539.
Inducing apoptosis is an effective treatment for cancer. Conventional cytotoxic anticancer agents induce apoptosis primarily through activation of tumor suppressor p53 by causing DNA damage and the resulting regulation of B-cell leukemia/lymphoma-2 (BCL-2) family proteins. Therefore, the effects of these agents are limited in cancers where p53 loss-of-function mutations are common, such as triple-negative breast cancer (TNBC). Here, we demonstrate that ultraviolet (UV) light-induced p53-independent transcriptional activation of NOXA, a proapoptotic factor in the BCL-2 family, results in apoptosis induction. This UV light-induced NOXA expression was triggered by extracellular signal-regulated kinase (ERK) activity. Moreover, we identified the specific UV light-inducible DNA element of the NOXA promoter and found that this sequence is responsible for transcription factor Krüppel-like factor 4 (KLF4)-mediated induction. In p53-mutated TNBC cells, inhibition of KLF4 by RNA interference reduced NOXA expression. Furthermore, treatment of TNBC cells with a KLF4-inducing small compound, APTO-253, resulted in the induction of NOXA expression and NOXA-mediated apoptosis. Therefore, our results help to clarify the molecular mechanism of DNA damage-induced apoptosis and provide support for a possible treatment method for p53-mutated cancers.
诱导细胞凋亡是治疗癌症的一种有效方法。传统的细胞毒性抗癌药物主要通过激活肿瘤抑制因子 p53 来诱导细胞凋亡，其方式是造成 DNA 损伤，并由此调节 B 细胞白血病/淋巴瘤-2（BCL-2）家族蛋白。因此，这些药物的效果在 p53 功能丧失突变常见的癌症中受到限制，例如三阴性乳腺癌（TNBC）。在这里，我们证明了紫外线（UV）光诱导的 p53 非依赖性转录激活 NOXA，即 BCL-2 家族中的促凋亡因子，会导致细胞凋亡。这种由细胞外信号调节激酶（ERK）活性引发的 UV 光诱导的 NOXA 表达。此外，我们鉴定了 NOXA 启动子的特定 UV 光诱导的 DNA 元件，发现该序列负责转录因子 Krüppel 样因子 4（KLF4）介导的诱导。在 p53 突变的 TNBC 细胞中，通过 RNA 干扰抑制 KLF4 会降低 NOXA 的表达。此外，用 KLF4 诱导的小分子化合物 APTO-253 处理 TNBC 细胞会导致 NOXA 表达和 NOXA 介导的凋亡。因此，我们的研究结果有助于阐明 DNA 损伤诱导的细胞凋亡的分子机制，并为治疗 p53 突变型癌症提供了一种可能的治疗方法。
