Targeting SMYD3 to Sensitize Homologous Recombination-Proficient Tumors to PARP-Mediated Synthetic Lethality
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Paola Sanese1, Candida Fasano1, Giacomo Buscemi2
1Medical Genetics, National Institute of Gastroenterology "S. de Bellis" Research Hospital, Castellana Grotte, Bari 70013, Italy.
Abstract:
SMYD3 is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical in vivo animal models. However, extensive characterization in vitro failed to clarify SMYD3 function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a SMYD3 mutant variant identified in a high-risk breast cancer family, here we show that SMYD3 phosphorylation by ATM enables the formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for the final loading of RAD51 at DNA double-strand break sites and completion of homologous recombination (HR). Remarkably, SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors, thereby extending the potential of the synthetic lethality approach in human tumors.
Insights
SMYD3 protein is crucial for cancer cell growth. Its phosphorylation by ATM facilitates DNA repair, and inhibiting SMYD3 sensitizes cancer cells to PARP inhibitors, offering a new synthetic lethality strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- SMYD3 is overexpressed in various cancers and crucial for tumor growth.
- Previous in vitro studies failed to fully elucidate SMYD3's function in cancer cells.
Purpose of the Study:
- To clarify the function of SMYD3 in cancer, particularly its role in DNA repair.
- To investigate the therapeutic potential of targeting SMYD3.
Main Methods:
- Utilized a SMYD3 mutant variant from a breast cancer family.
- Investigated the formation of multiprotein complexes involved in DNA double-strand break repair.
- Assessed the effect of SMYD3 inhibition on cancer cell sensitivity to PARP inhibitors.
Main Results:
- SMYD3 phosphorylation by ATM is essential for forming a complex with ATM, CHK2, and BRCA2.
- This complex is required for RAD51 loading and homologous recombination (HR) repair completion.
- Pharmacological inhibition of SMYD3 sensitizes HR-proficient cancer cells to PARP inhibitors.
Conclusions:
- SMYD3 plays a critical role in homologous recombination repair through its interaction with ATM, CHK2, and BRCA2.
- Targeting SMYD3 offers a promising synthetic lethality strategy for treating HR-proficient cancers.
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