TY - JOUR
T1 - Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis
AU - Casanova, Alexandre G.
AU - Roth, Gael S.
AU - Hausmann, Simone
AU - Lu, Xiaoyin
AU - Bischoff, Ludivine J.M.
AU - Froeliger, Emilie M.
AU - Belmudes, Lucid
AU - Bourova-Flin, Ekaterina
AU - Flores, Natasha M.
AU - Benitez, Ana Morales
AU - Chasan, Tourkian
AU - Caporicci, Marcello
AU - Vayr, Jessica
AU - Blanchet, Sandrine
AU - Ielasi, Francesco
AU - Rousseaux, Sophie
AU - Hainaut, Pierre
AU - Gozani, Or
AU - Le Romancer, Muriel
AU - Couté, Yohann
AU - Palencia, Andres
AU - Mazur, Pawel K.
AU - Reynoird, Nicolas
N1 - Publisher Copyright:
© 2024, The Author(s).
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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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U2 - 10.1038/s41421-023-00644-x
DO - 10.1038/s41421-023-00644-x
M3 - Article
C2 - 38296970
AN - SCOPUS:85183670853
SN - 2056-5968
VL - 10
JO - Cell Discovery
JF - Cell Discovery
IS - 1
M1 - 12
ER -