Diosgenin Inhibits Prostate Cancer Progression by Inducing UHRF1 Protein
Degradation
Abstract
Background and Purpose: Aberrant overexpression of UHRF1 has been
reported in several cancer types and UHRF1 is regarded as a novel drug
target for cancer therapy. However, no UHRF1-targeted specific small
compound inhibitor has been registered in clinical trials. Experimental
Approach: Network pharmacology together with molecular docking were used
to screened a natural molecule bank for PCa treatment. The expression of
related protein or mRNA were evaluated by WB and RT-PCR. The
ubiquitination levels were assessed by WB. CCK8 assess was used to
measuring cells viability. Additionally, PCa cells cycle were analysed
by cytofluorimetry, genomic DNA methylation was assessed by Dot blot
analysis. Cellular senescence was assessed by Senescence-Associated
β-Galactosidase Staining Kit. DU145 cell xenograft models were used to
assess the in vivo effect of DSG inhibition. Key Results: Identified DSG
as a new natural compound specifically targeting UHRF1 protein
degradation through the ubiquitin-proteasome pathway, DSG-induced UHRF1
protein degradation reduced the level of genomic DNA methylation, and
re-activated the expression of such TSGs as p21, p16 and LXN, thereby
resulted in cell cycle arrest, cell senescence and reduced DU145
xenograft tumor growth. Altogether, clarified DSG anticancer mechanism
as an epigenetic regulatory drug for the treatment of PCa. Conclusions
and Implications: Our results first time identified DSG which extract
from natural plants specifically targeting UHRF1 protein. This vpresent
study provided a promising strategy to discover new molecule-targeted
drug from natural compounds. KEYWORDS: Traditional Chinese Medicine;
Prostate cancer; Diosgenin; DNA methylation; Tumor suppressor genes;