Fang Huan, Liang Huichun, Yang Chuanyu, Jiang Dewei, Luo Qianmei, Cao Wen-Ming, Zhang Huifeng, Chen Ceshi
Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
Kunming College of Life Sciences, University of Chinese Academy of Sciences, Kunming, China.
Elife. 2025 Apr 10;13:RP102433. doi: 10.7554/eLife.102433.
In the clinic, anti-tumor angiogenesis is commonly employed for treating recurrent, metastatic, drug-resistant triple-negative, and advanced breast cancer. Our previous research revealed that the deubiquitinase STAMBPL1 enhances the stability of MKP-1, thereby promoting cisplatin resistance in breast cancer. In this study, we discovered that STAMBPL1 could upregulate the expression of the hypoxia-inducible factor HIF1α in breast cancer cells. Therefore, we investigated whether STAMBPL1 promotes tumor angiogenesis. We demonstrated that STAMBPL1 increased transcription in a non-enzymatic manner, thereby activating the HIF1α/VEGFA signaling pathway to facilitate triple-negative breast cancer angiogenesis. Through RNA-seq analysis, we identified the transcription factor GRHL3 as a downstream target of STAMBPL1 that is responsible for mediating transcription. Furthermore, we discovered that STAMBPL1 regulates transcription by interacting with the transcription factor FOXO1. These findings shed light on the role and mechanism of STAMBPL1 in the pathogenesis of breast cancer, offering novel targets and avenues for the treatment of triple-negative and advanced breast cancer.
在临床上，抗肿瘤血管生成通常用于治疗复发性、转移性、耐药性三阴性和晚期乳腺癌。我们之前的研究表明，去泛素化酶STAMBPL1可增强MKP-1的稳定性，从而促进乳腺癌中的顺铂耐药性。在本研究中，我们发现STAMBPL1可上调乳腺癌细胞中缺氧诱导因子HIF1α的表达。因此，我们研究了STAMBPL1是否促进肿瘤血管生成。我们证明，STAMBPL1以非酶促方式增加转录，从而激活HIF1α/VEGFA信号通路以促进三阴性乳腺癌血管生成。通过RNA测序分析，我们确定转录因子GRHL3是STAMBPL1的下游靶点，负责介导转录。此外，我们发现STAMBPL1通过与转录因子FOXO1相互作用来调节转录。这些发现揭示了STAMBPL1在乳腺癌发病机制中的作用和机制，为三阴性和晚期乳腺癌的治疗提供了新的靶点和途径。
