Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis

TL;DR

This study identifies SMYD2 as a key driver of breast cancer metastasis and suggests targeting it could prevent cancer spread.

Contribution

The study reveals SMYD2's role in metastasis through BCAR3 methylation and FMNL recruitment, offering a new therapeutic target.

Findings

SMYD2 is not required for primary tumor growth but is crucial for metastasis.

SMYD2 methylates BCAR3 at K334, which is recognized by FMNL proteins to modulate cell migration.

Pharmacologic inhibition of SMYD2 impairs metastasis in breast cancer models.

Abstract

Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cell dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cell ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiological substrate of SMYD2 in breast cancer cells. BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl-binding domain present in FMNLs proteins. These actin cytoskeleton regulators are recruited at the cell edges by the SMYD2 methylation signaling and modulate lamellipodia properties. Breast cancer cells with impaired BCAR3 methylation lose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo. Remarkably, SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis.

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