Lysine methyltransferase SMYD2 enhances androgen receptor signaling to modulate CRPC cell resistance to enzalutamide

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Androgen receptors (ARs) are critical in prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) drug resistance.
• SET and MYND domain containing protein 2 (SMYD2) is a lysine methyltransferase implicated in tumor promotion.
• The specific role of SMYD2 in CRPC drug resistance is not well understood.

Purpose of the Study:

• To investigate the role of SMYD2 in PCa progression and CRPC resistance to enzalutamide.
• To elucidate the molecular mechanisms by which SMYD2 influences AR signaling and CRPC phenotypes.
• To evaluate the therapeutic potential of targeting SMYD2 in CRPC.

Main Methods:

• Analysis of SMYD2 expression in PCa tissues and cell lines.
• In vitro studies involving SMYD2 knockdown and overexpression in CRPC cell lines (22Rv1, C4-2).
• Assessment of cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT).
• Investigation of AR methylation, phosphorylation, ubiquitination, and proteasome degradation.
• Evaluation of the synergistic effect of SMYD2 inhibitor AZ505 with enzalutamide in cell lines and mouse models.

Main Results:

• SMYD2 expression is significantly upregulated in PCa and correlates with poor patient survival.
• SMYD2 knockdown inhibits CRPC cell proliferation, migration, invasion, and EMT, while overexpression promotes these.
• SMYD2 directly methylates and phosphorylates ARs, impacting AR ubiquitination and proteasome degradation.
• SMYD2 inhibition with AZ505 shows synergistic effects with enzalutamide and re-sensitizes resistant CRPC cells.

Conclusions:

• SMYD2 enhances AR methylation and phosphorylation, affecting AR degradation and modulating CRPC resistance to enzalutamide.
• SMYD2 acts as a crucial oncogene in PCa.
• SMYD2 represents a promising therapeutic target for overcoming enzalutamide resistance in CRPC.