2. Academic Validation
  3. Targeting USP28 inhibits clear cell renal cell carcinoma growth

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

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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