Total Flavonoids of Hedyotis Diffusa Willd Suppresses Prostate Cancer Progression by Promoting AR Ubiquitination and Degradation via the PIAS4/STAT3 Pathway

Abstract

Total flavonoids of Hedyotis diffusa Willd (TFHDW) is an active compound extracted from Hedyotis diffusa Willd (HDW), one of the most well-known herbs possessing antitumor effects. In this study, the potential antitumor effects of TFHDW were investigated in vitro in mouse prostate cancer cells RM1 and human prostate cancer cells LNCaP and in vivo using a xenograft tumor model involving injection of RM1 cells. Upon TFHDW treatment, RM1 and LNCaP cells exhibited augmented protein expression of the protein inhibitor of activated STAT (PIAS4) and diminished activity of signal transducer and activator of transcription 3 (STAT3), along with impaired proliferative, migratory, and invasive capacities. Ectopic STAT3 expression or PIAS4 silencing in RM1 and LNCaP cells partly annulled the inhibition effect of TFHDW treatment on cell malignant phenotypes. Mechanistic studies revealed that TFHDW elevated transcriptional activity of damage-specific DNA-binding protein 2 via PIAS4/STAT3, consequently enhancing ubiquitination and degradation of androgen receptor (AR) protein. By this, TFHDW alleviated the growth of prostate cancer in vitro and in vivo. Altogether, our work uncovers new insights into the link between TFHDW and the PIAS4/STAT3/AR axis in prostate cancer. These findings may provide a novel therapeutic option for targeting the PIAS4/STAT3/AR axis in prostate cancer.