Liu Kun, Gao Qiong, Jia Yuzhi, Wei Juncheng, Chaudhuri Shuvam Mohan, Wang Shengnan, Tang Amy, Mani Nikita Lavanya, Iyer Radhika, Cheng Yang, Gao Beixue, Lu Weiyuan, Sun Zhaolin, Zhang Bin, Liu Huiping, Fang Deyu
Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, P.R. China.
iScience. 2024 Jul 27;27(9):110592. doi: 10.1016/j.isci.2024.110592. eCollection 2024 Sep 20.
Integrins play critical roles in connecting the extracellular matrix and actin. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that USP22 is essential in maintaining breast cancer cell stemness by promoting the transcription of integrin β1 (). Both genetic and pharmacological inhibition of USP22 largely impaired breast CSCs self-renewal and prevented their metastasis. Reconstitution of integrin β1 partially rescued USP22-null breast cancer metastasis. USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral gene transcription. Immunohistochemistry staining detected a positive correlation among USP22, FoxM1, and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis as critical for cancer stemness and offers a potential target for antitumor therapy.
整合素在连接细胞外基质和肌动蛋白方面发挥着关键作用。虽然整合素的上调被认为会促进癌症干性和转移，但其在癌症干细胞（CSCs）中上调的机制仍知之甚少。在此，我们表明USP22通过促进整合素β1的转录对维持乳腺癌细胞干性至关重要。对USP22的基因抑制和药物抑制在很大程度上损害了乳腺CSCs的自我更新并阻止了它们的转移。整合素β1的重建部分挽救了USP22缺失的乳腺癌转移。USP22作为一种真正的去泛素化酶，保护叉头框M1（FoxM1）的蛋白酶体降解，FoxM1是肿瘤基因转录的转录因子。免疫组织化学染色检测到在人类乳腺癌中USP22、FoxM1和整合素β1之间呈正相关。总的来说，我们的研究确定USP22-FoxM1-整合素β1信号轴对癌症干性至关重要，并为抗肿瘤治疗提供了一个潜在靶点。
