Abstract 2764: Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness & metastasis

Abstract Integrins play critical roles in connecting the extracellular matrix and actin skeleton for cell adhesion, migration, signal transduction, and gene transcription. 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 the death from cancer signature gene, USP22, is essential in maintaining breast cancer cell stemness by promoting the transcription of a group of integrin family members, in particular, integrin β1 (ITGB1). Both genetic and pharmacological inhibition of USP22 largely impaired breast cancer stem cell self-renewal and prevented their metastasis. Reconstitution of Integrin β1 partially rescued USP22-null breast cancer stemness and their metastasis. At the molecular level, USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Importantly, unbiased analysis of the TCGA database revealed a strong positive correlation between USP22 and ITGB1 in more than 90% of human cancer types, implying that USP22 functions as a key factor in maintaining stemness across a broad spectrum of human cancer types possibly through regulating ITGB1. To support this notion, 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. Citation Format: Qiong Gao, Kun Liu, Yuzhi Jia, Juncheng Wei, Shuvam Mohan Chaudhuri, Shengnan Wang, Amy Tang, Nikita Lavanya Mani, Radhika Iyer, Yang Cheng, Beixue Gao, Weiyuan Lu, Zhaolin Sun, Huiping Liu, Deyu Fang. Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness & metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2764.