Zhang Zhilei, Wang Yonghua, Liang Zhijuan, Meng Zhaoyuan, Zhang Xiangyan, Ma Guofeng, Chen Yuanbin, Zhang Mingxin, Su Yinjie, Li Zhiqiang, Liang Ye, Niu Haitao
Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China.
Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.
iScience. 2023 Oct 5;26(11):108142. doi: 10.1016/j.isci.2023.108142. eCollection 2023 Nov 17.
ALDH1A1 is one of the classical stem cell markers for bladder cancer. Lysine 2-hydroxyisobutyrylation (Khib) is a newfound modification to modulate the protein expression, and the underlying mechanisms of how ALDH1A1 was regulated by Khib modification in bladder cancer remains unknown. Here, ALDH1A1 showed a decreased K260hib modification, as identified by protein modification omics in bladder cancer. Decreasing ALDH1A1 expression significantly suppressed the proliferation, migration and invasion of bladder cancer cells. Moreover, K260hib modification is responsible for the activity of ALDH1A1 in bladder cancer, which is regulated by HDAC2/3. Higher K260hib modification on ALDH1A1 promotes protein degradation through chaperone-mediated autophagy (CMA), and ALDH1A1 K260hib could sensitize bladder cancer cells to chemotherapeutic drugs. Higher ALDH1A1 expression with a lower K260hib modification indicates a poor prognosis in patients with bladder cancer. Overall, we demonstrated that K260hib of ALDH1A1 can be used as a potential therapeutic target for bladder cancer treatment.
醛脱氢酶1A1（ALDH1A1）是膀胱癌的经典干细胞标志物之一。赖氨酸2-羟基异丁酰化（Khib）是一种新发现的可调节蛋白质表达的修饰，而在膀胱癌中，Khib修饰如何调控ALDH1A1的潜在机制仍不清楚。在此，通过膀胱癌中的蛋白质修饰组学鉴定发现，ALDH1A1的K260hib修饰降低。降低ALDH1A1的表达可显著抑制膀胱癌细胞的增殖、迁移和侵袭。此外，K260hib修饰决定了ALDH1A1在膀胱癌中的活性，其受组蛋白去乙酰化酶2/3（HDAC2/3）调控。ALDH1A1上较高的K260hib修饰通过伴侣介导的自噬（CMA）促进蛋白质降解，并且ALDH1A1 K260hib可使膀胱癌细胞对化疗药物敏感。ALDH1A1表达较高而K260hib修饰较低表明膀胱癌患者预后较差。总体而言，我们证明了ALDH1A1的K260hib可作为膀胱癌治疗的潜在靶点。
