Targeting G-quadruplexes of PBX1 by antisense oligonucleotide for melanoma therapyPBX1_OE_2
Abnormal PBX1 expression plays a key role in tumorigenesis. However, the clinical impact of PBX1 on melanoma and the underlying mechanisms regulating PBX1 expression in melanoma are not fully known. In this study, we showed that PBX1 is up-regulated in melanoma and its high expression predicts poor prognosis. Furthermore, we confirmed that G-rich regions derived from the promoter and transcripts of PBX1 can form stable G-quadruplexes (G4s). Importantly, the formation of PBX1 G4s, which is induced by G4 stabilizing compounds or specific antisense oligodeoxynucleotide (ASO), significantly inhibits the melanoma growth and metastasis by downregulating the PBX1 expression. Mechanistically, PBX1 DNA G4 formation blocks Zic2 occupancy in PBX1 promoter regions to inhibit the transcription of PBX1. Our findings collectively revealed the clinical impact of PBX1 on melanoma and a novel regulatory mechanism for governing PBX1 expression and provided an out-of-the-box G4-targeting therapeutic strategy for melanoma.