Abstract 147: Targeting USP22 suppresses tumorigenicity and enhances sensitivity to cisplatin in cancer-initiating cells from lung adenocarcinoma through downregulating ALDH1A3

We previously found that loss of monoubiquitination of histone H2B (H2Bub1) was associated with poor differentiation and enhanced malignancy of lung adenocarcinoma. Herein, we investigated the expression and roles of USP22, an H2Bub1 deubiquitinase, in cancer-initiating cells (CICs) with stem cell-like characteristics from primary lung adenocarcinoma. CICs from patient-derived cancer tissues were isolated and characterized, and the association of USP22 with CICs was investigated using flow cytometry, aldehyde dehydrogenase (ALDH) activity, Western blot, and fluorescence microscope assays. The impact of USP22 on stem cell-like characteristics and cisplatin resistance in CICs was examined by in vitro tumorsphere formation, in vivo transplantation, and apoptosis assays. We identified that USP22 is predominantly expressed in CICs, a subpopulation of cells with high expression of CD133 stem cell biomarker. The expression of USP22 in CICs is dramatically reduced upon serum-induced differentiation. Moreover, knockdown of USP22 significantly suppressed in vitro tumorsphere formation and in vivo xenograft growth in NOD-SCID mice. Notably, USP22 is dramatically elevated in tumorsphere cells that survived cisplatin treatment, while knockdown of USP22 significantly sensitizes tumorsphere cells to cisplatin. Interestingly, ALDH1A3, a dominant isoform of ALDH implicated in enhancing cisplatin resistance in lung adenocarcinoma, is significantly downregulated upon knockdown of USP22 in tumorsphere cells. Furthermore, knockdown of ALDH1A3 significantly sensitizes tumorsphere cells to cisplatin. Therefore, our data indicate that USP22 plays critical roles in tumorigenicity and cisplatin resistance in lung adenocarcinoma, and targeting USP22 may represent a potential therapeutic approach to eliminate CICs in lung adenocarcinoma through downregulation of ALDH1A3 expression. Citation Format: Keqiang Zhang, Xinwei Yun, Jinhui Wang, Melisa Bonner, Lu Yang, Jun Wu, Dan J. Raz. Targeting USP22 suppresses tumorigenicity and enhances sensitivity to cisplatin in cancer-initiating cells from lung adenocarcinoma through downregulating ALDH1A3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 147.