TRIM21-mediated ubiquitination of PARP1 regulated by the PI3K/AKT-STAT5A axis suppresses small cell lung cancer

Abstract Abnormal accumulation of Poly(ADP-ribose) polymerase 1 (PARP1) promotes cancer progression, yet its stabilization mechanisms remain unclear. Here, we identify E3 ubiquitin ligase tripartite motif-containing 21 (TRIM21) as a PARP1-binding partner. PARP1 interacts directly with TRIM21 via its 662-908 domain, while the PRY-SPRY domain of TRIM21 is essential for this binding. TRIM21 facilitates PARP1 polyubiquitination at residue K654, leading to its degradation. In small cell lung cancer (SCLC), TRIM21 is significantly downregulated, and its tumor-suppressive function is partly mediated through the degradation of PARP1, supporting genomic stability. Additionally, the PI3K/AKT pathway transcriptionally suppresses TRIM21 via transcription factor STAT5A, thereby stabilizing PARP1. Importantly, combining the PI3K/AKT inhibitor PKI-587 with the PARP inhibitor BMN673 synergistically inhibits tumor growth across multiple SCLC models, including cell lines, patient-derived organoids, and xenograft models. Collectively, our findings define a “PI3K/AKT-STAT5A-TRIM21-PARP1” axis critical for SCLC progression and propose its dual inhibition as a promising therapeutic strategy.

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Publication Details

Journal
Nature Communications
Published
2026-06-18
DOI
https://doi.org/10.1038/s41467-026-73271-1
Primary Topic
Lung Cancer Research Studies
Type
article
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article

TRIM21-mediated ubiquitination of PARP1 regulated by the PI3K/AKT-STAT5A axis suppresses small cell lung cancer

Xinhuang Yao, Chenchen Guo, Wenchu Lin, Li Xiang et al.
Nature Communications
Lung Cancer Research Studies
article

TRIM21-mediated ubiquitination of PARP1 regulated by the PI3K/AKT-STAT5A axis suppresses small cell lung cancer

Xinhuang Yao, Chenchen Guo, Wenchu Lin, Li Xiang, Gongfeng Li, Jiahui Zhang, Xiaolin Wang, Guozhen Cao, Xiaopeng Guo, Yi-Xiang Wang, Hongbin Ji, Peng Hou, Tengfei Zhang
article en

Abstract

Abstract Abnormal accumulation of Poly(ADP-ribose) polymerase 1 (PARP1) promotes cancer progression, yet its stabilization mechanisms remain unclear. Here, we identify E3 ubiquitin ligase tripartite motif-containing 21 (TRIM21) as a PARP1-binding partner. PARP1 interacts directly with TRIM21 via its 662-908 domain, while the PRY-SPRY domain of TRIM21 is essential for this binding. TRIM21 facilitates PARP1 polyubiquitination at residue K654, leading to its degradation. In small cell lung cancer (SCLC), TRIM21 is significantly downregulated, and its tumor-suppressive function is partly mediated through the degradation of PARP1, supporting genomic stability. Additionally, the PI3K/AKT pathway transcriptionally suppresses TRIM21 via transcription factor STAT5A, thereby stabilizing PARP1. Importantly, combining the PI3K/AKT inhibitor PKI-587 with the PARP inhibitor BMN673 synergistically inhibits tumor growth across multiple SCLC models, including cell lines, patient-derived organoids, and xenograft models. Collectively, our findings define a “PI3K/AKT-STAT5A-TRIM21-PARP1” axis critical for SCLC progression and propose its dual inhibition as a promising therapeutic strategy.

Nature Communications
University of Science and Technology of China (CN), Shanghai Jiao Tong University (CN), Chinese Academy of Sciences (CN), Lanzhou University of Technology (CN), Shanghai Chest Hospital (CN), Westlake University (CN), High Magnetic Field Laboratory (CN), Chinese University of Hong Kong, Shenzhen (CN), Center for Excellence in Molecular Cell Science (CN), University of Hong Kong - Shenzhen Hospital (CN), Shenzhen Second People's Hospital (CN), University of Chinese Academy of Sciences (CN)
Good health and well-being
Openalex Percentile: Top 8%
Lung Cancer Research Studies
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