ArticleProceedings of the National Academy of Sciences of the United States of America2024
TRIM21 induces selective autophagic degradation of c-Myc and sensitizes regorafenib therapy in colorectal cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- Metabolic reprogramming in colorectal cancer: Mechanisms and therapeutic insights.Genes & diseases · 2027Review
- KRAS/ERK2-driven stabilization of AARS1 reprograms tumor metabolism and confers Sorafenib resistance in lung adenocarcinoma.Cell death and differentiation · 2026Article
- Unraveling the Multifaceted Role of TRIM21 in Virus-Triggered Innate Immunity and Diseases.Biomolecules · 2026Review
- XPO1-mediated TRIM21 nuclear export reprograms TREM2+ macrophage polarization by targeting IRF3 to augment anti-PD-1 efficacy in small cell lung cancer.Nature communications · 2026Article
- Targeting the NAT1-ENO1-Lactate Axis Destabilizes PD-L1 to Reinvigorate Antitumor Immunity in Colorectal Cancer.MedComm · 2026Article
- Synergistic mechanisms and clinical translation of regorafenib combination therapies.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- TRIM21-mediated ubiquitination of PARP1 regulated by the PI3K/AKT-STAT5A axis suppresses small cell lung cancer.Nature communications · 2026Article
- Tumor-enriched circRNA TAFCR1 drives cancer progression and metastasis by disrupting UBE1-dependent TRIM21-mediated CD44 ubiquitination.Biomarker research · 2026Article
- ADCY7 dictates N-cadherin stability to inhibit HCC metastasis.JHEP reports : innovation in hepatology · 2026Article
- Mechanisms of TRIM21-mediated RUNX2 degradation via chaperone-mediated autophagy in periodontitis.Cell biology and toxicology · 2026Article
- USP43 Inhibits Intestinal Inflammation via TRAF4-mediated NF-κB Signaling.Inflammation · 2026Article
- Macrophage TRIM21 Inhibition Ameliorates Murine Acute Pancreatitis via PHB2-Mediated Mitochondrial Stabilization.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- PVT1-104aa derived from the 8q24 gene desert promotes colorectal cancer tumorigenesis.Clinical and translational medicine · 2026Article
- Extracellular CD44 lactylation impairs CD8Nature metabolism · 2026Article
- Unraveling regorafenib resistance: metabolic reprogramming, tumor plasticity, and novel approaches to overcome therapy failure.Archives of pharmacal research · 2026Review
- TRIM21 is a molecular rheostat for influenza A virus replication.bioRxiv : the preprint server for biology · 2026Article
- Functional characterization of CASP, aiScience · 2026Article
- Targeting the autophagic network: A new frontier in colorectal cancer chemotherapy response.CytoJournal · 2026Article
- Dual targeting of the UPS and autophagy as a novel therapy for neurodegenerative proteinopathies.Frontiers in cellular neuroscience · 2026Review
- Intra-tumoural microenvironment and bugs-based drug design: foreseeable future in oncology and immuno-oncology.Frontiers in pharmacology · 2026Review
Corrections and comments
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Authors and funding
20 authors.
Funding
Abstract
Kirsten rat sarcoma virus (KRAS) mutation is associated with malignant tumor transformation and drug resistance. However, the development of clinically effective targeted therapies for KRAS-mutant cancer has proven to be a formidable challenge. Here, we report that tripartite motif-containing protein 21 (TRIM21) functions as a target of extracellular signal-regulated kinase 2 (ERK2) in KRAS-mutant colorectal cancer (CRC), contributing to regorafenib therapy resistance. Mechanistically, TRIM21 directly interacts with and ubiquitinates v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) at lysine 148 (K148) via K63-linkage, enabling c-Myc to be targeted to the autophagy machinery for degradation, ultimately resulting in the downregulation of enolase 2 expression and inhibition of glycolysis. However, mutant KRAS (KRAS/MT)-driven mitogen-activated protein kinase (MAPK) signaling leads to the phosphorylation of TRIM21 (p-TRIM21) at Threonine 396 (T396) by ERK2, disrupting the interaction between TRIM21 and c-Myc and thereby preventing c-Myc from targeting autophagy for degradation. This enhances glycolysis and contributes to regorafenib resistance. Clinically, high p-TRIM21 (T396) is associated with an unfavorable prognosis. Targeting TRIM21 to disrupt KRAS/MT-driven phosphorylation using the antidepressant vilazodone shows potential for enhancing the efficacy of regorafenib in treating KRAS-mutant CRC in preclinical models. These findings are instrumental for KRAS-mutant CRC treatment aiming at activating TRIM21-mediated selective autophagic degradation of c-Myc.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.