Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression
Zhilei Zhang,
Yonghua Wang,
Zhijuan Liang,
Zhaoyuan Meng,
Xiangyan Zhang,
Guofeng Ma,
Yuanbin Chen,
Mingxin Zhang,
Yinjie Su,
Zhiqiang Li,
Ye Liang,
Haitao Niu
Affiliations
Zhilei Zhang
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
Yonghua Wang
Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
Zhijuan Liang
Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
Zhaoyuan Meng
School of Basic Medicine, Qingdao University, No.308 Ningxia Road, Qingdao 266071, China
Xiangyan Zhang
Department of Pathology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
Guofeng Ma
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
Yuanbin Chen
Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China
Mingxin Zhang
Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
Yinjie Su
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
Zhiqiang Li
The Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao 266071, China
Ye Liang
Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China; Corresponding author
Haitao Niu
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; Corresponding author
Summary: 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.
