Targeting USP28 inhibits clear cell renal cell carcinoma growth

  • Cell Signal. 2025 Dec 26:139:112344. doi: 10.1016/j.cellsig.2025.112344.
Ying Ren  1 ,  Yunfang Yang  2 ,  Xiaodan Zhu  3 ,  Lingyi Li  1 ,  Yaoyao Pan  1 ,  Hong Sun  4 ,  Qian Fang  4 ,  Hui Xiong  5 ,  Dong Guo  1 ,  Yongzhan Sun  6 ,  Hailong Li  7 ,  Junqi Wang  8
Affiliations
  • 1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China.
  • 2. Department of Urology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China; Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China.
  • 3. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China; Huai'an 82 Hospital, Huai'an 223001, Jiangsu, China.
  • 4. Department of Urology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China.
  • 5. Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China.
  • 6. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China. Electronic address: [email protected].
  • 7. Department of Urology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China; The First Clinical Medical College of Xuzhou Medical University, Xuzhou 221004, Jiangsu, China. Electronic address: [email protected].
  • 8. Department of Urology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China. Electronic address: [email protected].
PMID: 41456627 DOI: 10.1016/j.cellsig.2025.112344
Abstract

Clear cell renal cell carcinoma (ccRCC), the most common type of kidney Cancer, remains challenging to treat due to the lack of effective targeted therapies. Although c-Myc is frequently overexpressed in ccRCC, the mechanisms governing its stability are not well understood. Here, we identify the deubiquitinating enzyme USP28 as a key regulator of c-Myc protein stability in ccRCC. USP28 interacts with c-Myc, removes K48-linked polyubiquitin chains, and thereby prevents its proteasomal degradation, leading to c-Myc stabilization in ccRCC cells. Genetic or pharmacological inhibition of USP28 significantly reduces c-Myc expression, impairs ccRCC cell proliferation in vitro, and suppresses tumor growth in vivo. Tumors with high c-Myc expression exhibit heightened sensitivity to USP28 inhibition, underscoring the therapeutic potential of targeting this axis. Collectively, our findings position USP28 as a promising therapeutic target for ccRCC.

Keywords
AZ1; C-Myc; USP28; Ubiquitin-proteasome system; ccRCC.
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