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

doi:10.1016/j.isci.2023.108142

Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression

iScience. 2023 Oct 5;26(11):108142. doi: 10.1016/j.isci.2023.108142. eCollection 2023 Nov 17.

Authors

Zhilei Zhang^{1

2}, Yonghua Wang¹, Zhijuan Liang², Zhaoyuan Meng³, Xiangyan Zhang⁴, Guofeng Ma^{1

2}, Yuanbin Chen², Mingxin Zhang¹, Yinjie Su^{1

2}, Zhiqiang Li⁵, Ye Liang², Haitao Niu^{1

2}

Affiliations

¹ Department of Urology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China.
² Key Laboratory, Department of Urology and Andrology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.
³ School of Basic Medicine, Qingdao University, No.308 Ningxia Road, Qingdao 266071, China.
⁴ Department of Pathology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China.
⁵ 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.

Abstract

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.

Keywords: Biochemistry; Cancer.