2. Academic Validation
  3. TRIB3 recruits and stabilizes CARM1 to confer chemoresistance by activating Akt signalling in clear cell renal cancer cells

TRIB3 recruits and stabilizes CARM1 to confer chemoresistance by activating Akt signalling in clear cell renal cancer cells

  • Biochem Biophys Res Commun. 2025 Jun 20:766:151827. doi: 10.1016/j.bbrc.2025.151827.
Danfei Hu 1,  Xiaodong Fan 2,  Xiaodong Chen 2,  Mingyao Li 1,  Huacai Xiong 1,  Xiaoxiao Fan 3,  Feng Chen 4
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang, PR China.
  • 2 Department of Urology, Ningbo Urology and Nephrology Hospital, Ningbo, Zhejiang, PR China.
  • 3 Department of Urology, Ningbo Urology and Nephrology Hospital, Ningbo, Zhejiang, PR China. Electronic address: nbdocfan@outlook.com.
  • 4 Department of Urology, Ningbo Urology and Nephrology Hospital, Ningbo, Zhejiang, PR China. Electronic address: zjsxkqcf@163.com.
PMID: 40286768 DOI: 10.1016/j.bbrc.2025.151827
Abstract

Sunitinib resistance remains a major obstacle in the treatment of clear cell renal cell carcinoma (ccRCC), yet the underlying mechanisms are poorly defined. Here, we identify a previously unrecognized axis involving Tribbles homolog 3 (TRIB3) and coactivator-associated arginine methyltransferase 1 (CARM1) that drives chemoresistance through modulation of Akt signaling. Mechanistically, TRIB3 directly interacts with CARM1, a pro-survival epigenetic regulator, and inhibits its ubiquitination to stabilize CARM1 protein levels. Elevated CARM1 further exacerbates therapeutic resistance, establishing a feedforward loop that sustains Akt activation. Our findings uncovering a novel TRIB3-CARM1-Akt axis as a central driver of sunitinib resistance. This study provides mechanistic insights into ccRCC chemoresistance and highlights therapeutic targeting of the TRIB3-CARM1 axis as a promising strategy to overcome treatment failure.

Keywords

Akt; CARM1; Sunitinib; TRIB3; ccRCC.

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