siRNA-based therapeutic candidate targeting PRDM2 for inhibition of lung cancer progression

Lung cancer is the leading cause of tumor-related deaths worldwide. In over 70 % of patients, the positive regulatory domain 2 (PRDM2) gene, which encodes the tumor suppressor RIZ1 and the oncogenic RIZ2 isoforms, is dysregulated, promoting tumor progression via RIZ2 overexpression. In this study, we used ARIZ-047, a siRNA designed to inhibit the effect of the oncogenic protein RIZ2 selectively. Inhibiting RIZ2 with ARIZ-047 treatment increased RIZ1 expression and decreased the viability of a lung cancer cell line (A549). Transcriptomic analysis after ARIZ-047 treatment revealed the modulation of the Wnt signaling pathway and downregulation of genes associated with proliferation and metastasis. In vivo, ARIZ-047 encapsulated in targeted nanoparticles (T-CaP) showed a marked reduction in tumor size and RIZ2 expression in a xenograft mouse model. In conclusion, this study identifies ARIZ-047 as a targeted therapy in lung cancer, which inhibits RIZ2 explicitly and suggests the role of the Wnt signaling pathway in RIZ2 overexpression.