Mutant TP53 interacts with BCAR1 to contribute to cancer cell invasion

Alvin Kunyao Guo,Hui Ying Chow,Yoko Itahana,Veerabrahma Pratap Seshachalam,Sujoy Ghosh,Koji Itahana

doi:10.1038/s41416-020-01124-9

Alvin Kunyao Guo, Hui Ying Chow + Show 4 more

Open Access

https://doi.org/10.1038/s41416-020-01124-9

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Abstract

BackgroundMutant TP53 interacts with other proteins to produce gain-of-function properties that contribute to cancer metastasis. However, the underlying mechanisms are still not fully understood.MethodsUsing immunoprecipitation and proximity ligation assays, we evaluated breast cancer anti-estrogen resistance 1 (BCAR1) as a novel binding partner of TP53R273H, a TP53 mutant frequently found in human cancers. The biological functions of their binding were examined by the transwell invasion assay. Clinical outcome of patients was analysed based on TP53 status and BCAR1 expression using public database.ResultsWe discovered a novel interaction between TP53R273H and BCAR1. We found that BCAR1 translocates from the cytoplasm into the nucleus and binds to TP53R273H in a manner dependent on SRC family kinases (SFKs), which are known to enhance metastasis. The expression of full-length TP53R273H, but not the BCAR1 binding-deficient mutant TP53R273HΔ102–207, promoted cancer cell invasion. Furthermore, among the patients with mutant TP53, high BCAR1 expression was associated with a poorer prognosis.ConclusionsThe interaction between TP53R273H and BCAR1 plays an important role in enhancing cancer cell invasion. Thus, our study suggests a disruption of the TP53R273H–BCAR1 binding as a potential therapeutic approach for TP53R273H-harbouring cancer patients.

Highlights

Mutant TP53 interacts with other proteins to produce gain-of-function properties that contribute to cancer metastasis
TP53R273H binds to breast cancer anti-estrogen resistance 1 (BCAR1) in the nucleus To uncover a novel mechanism by which mutant TP53 exhibits its gain-of-function properties, we looked for TP53R273H interacting proteins that contribute to cancer cell invasion
Consistent with 3D spheroid invasion assay (Fig. 2b, c), the invasiveness of U251MG cells measured by transwell assay was similar when TP53R273H and BCAR1 were depleted simultaneously or individually (Fig. 2d, e). We confirmed this observation in another cancer cell line, A431 cells (TP53R273H-harbouring human epidermoid carcinoma cell line24) (Supplementary Fig. S3). These results suggest that TP53R273H and BCAR1 may contribute to cancer cell invasion in the same pathway

Summary

Introduction

Mutant TP53 interacts with other proteins to produce gain-of-function properties that contribute to cancer metastasis. Mutation within the DNA-binding domain often leads to the loss of DNA-binding ability of TP53 Such mutant TP53 is unable to induce CDKN1A, BBC3/PUMA and BAX to trigger tumoursuppressive functions, and the mutations in TP53 have been known to be similar with deletion of TP53, often referred to as the loss-of-function of TP53.4,5 in vivo knock-in mice harbouring mutant forms of Trp[53] (mouse orthologue corresponding to human TP53) developed more metastatic tumours as compared to Trp53-null mice.[9,10] TP53 is mutated more in the advanced stage of human cancers, compared to the early stages, suggesting that mutant TP53 is involved in metastasis in human cancer as well.[11,12] These findings shifted the paradigm of understanding of TP53 mutations.

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