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Coexistence of P53 and KRAS mutations enhances ERK1/2 signaling by inducing EGR1 expression through mutp53 and c-JUN interaction

Oncogene volume 44, pages 3787–3798 (2025)Cite this article

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Abstract

The ERK1/2 signaling pathway, one of the most frequently dysregulated oncogenic pathways, can be initiated by diverse mutations, including those in RAS, BRAF, and amplifications of ERBB2 (HER2). Co-occurrence of ERK1/2 hyperactivation and TP53 mutations is common in multiple cancer types and correlates with significantly poorer clinical outcomes. However, the direct mechanisms underlying the cooperation between ERK1/2 signaling and mutant p53 remain largely unexplored. Our study demonstrates that oncogenic KRAS activates c-JUN, which facilitates physical interactions with mutant p53, leading to hyperactivation of several pro-metastatic transcriptional networks. Notably, mutant p53 and c-JUN collaboratively upregulate EGR1, a key driver of tumor invasion and metastasis. The combined effects of elevated EGR1 expression, along with signaling pathways activated by KRAS and mutant p53, significantly enhance pro-metastatic traits in cancer cells. These findings provide crucial insights into the co-enrichment of KRAS and p53 mutations and pave the way for novel therapeutic strategies targeting this interaction.

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Fig. 1: GSEA analysis in the exploration cohort, utilizing datasets GSE65458 (for SUM-149PT and BT-549), GSE68248 (for MDA-MB-231) and GSE291033 (for PANC-1).
Fig. 2: Identification of EGR1 as a target gene of mutant p53 and KRAS.
Fig. 3: Mutant p53 promotes cell migration and pro-invasive via EGR1.
Fig. 4: c-JUN occupies the EGR1 gene promoter in KRAS mutant cells.
Fig. 5: Tp53 colocalizes with c-JUN in cells with coexisting TP53 and KRAS mutations.
Fig. 6: EGR1 expression levels correlate with GOFp53 in PAAD.
Fig. 7: Mutant p53 cooperates with oncogenic KRAS effectors to generate metastatic phenotypes.

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Data availability

The RNA sequencing data generated from mutant p53 knockdown experiments in this study are available in the GEO Repository under accession numbers GSE65458, GSE68248, and GSE291033. For ChIP-seq data: MDA-MB-231 cell line: p53 and c-JUN data are accessible through GEO (GSE66543, GSE66081). A549 cell line: p53 (ENCFF877LNP) and c-JUN (ENCFF957TUK) data are available via ENCODE. HepG2 cell line: p53 and c-JUN data can be found in ENCODE under accession number ENCFF784KMC (p53) and ENCFF732BEG(c-JUN).

Code availability

The custom code and scripts used for data analysis in this study are available from the corresponding author upon reasonable request. All software packages and publicly available tools utilized in this work are cited in the Methods section, along with their respective version numbers and accessibility information.

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Acknowledgements

This work was supported Science and Technology Fund of Tianjin Municipal Health Commission (NO. TJWJ2022QN098).

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  1. These authors contributed equally: Manxue Wang, Ailing Ji.

Authors and Affiliations

  1. Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin, China

    Manxue Wang, Ailing Ji, Ruifang Gao & Sike Hu

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Contributions

MXW and ALJ performed the experiments and data analysis. RFG performed data analysis. SKH designed the study and wrote the manuscript. MXW acquired the funding. All authors edited and revised the manuscript and were involved in the final approval of the manuscript.

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Correspondence to Sike Hu.

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The authors declare no competing interests.

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This study did not involve human participants, human tissue, or live vertebrate animals. All analyses were conducted using publicly available datasets and computational modeling techniques. Therefore, ethical approval from our institutional ethics committee and informed consent were not required for this research.

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Wang, M., Ji, A., Gao, R. et al. Coexistence of P53 and KRAS mutations enhances ERK1/2 signaling by inducing EGR1 expression through mutp53 and c-JUN interaction. Oncogene 44, 3787–3798 (2025). https://doi.org/10.1038/s41388-025-03536-4

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