Propolin G induces G1 cell cycle arrest through class I HDAC–dependent p21Waf1/Cip1 upregulation in breast cancer cells

This study investigated the antiproliferative effects and epigenetic mechanisms of propolin G, a C-prenylflavanone derived from Taiwanese propolis, across three breast cancer subtypes (BT474, MCF-7, and MDA-MB-231). Cell viability, cell cycle distribution, and histone deacetylase (HDAC) activity were analyzed. Propolin G exhibited dose-dependent inhibitory effects in breast cancer cells, with IC₅₀ values of 10.14 μM and 13.51 μM in BT474 and MDA-MB-231 cells, respectively, while MCF-7 cells were relatively less sensitive (IC₅₀ > 20 μM). Compared to normal MCF10A cells (IC₅₀ > 20 μM), the Selectivity Index (SI) was >1.97 for BT474 and > 1.48 for MDA-MB-231, demonstrating preferential cytotoxicity toward malignant cells. Mechanistically, propolin G acted as a natural Class I HDAC inhibitor, increasing acetylation of histones H3 and H4, which led to the transcriptional reactivation of p21 Waf1/Cip1 . The functional necessity of p21 Waf1/Cip1 was confirmed via siRNA knockdown, which attenuated the growth-inhibitory effects. Chromatin immunoprecipitation analysis further verified enhanced histone acetylation at the p21 Waf1/Cip1 promoter region. Collectively, these findings provide novel mechanistic insights into the epigenetic actions of propolin G and underscore its potential as a promising dietary agent for breast cancer chemoprevention and functional food development. • Propolin G inhibits growth in BT474, MCF-7, and MDA-MB-231 breast cancer cells. • Propolin G acts as a natural inhibitor of class I histone deacetylases (HDACs). • Propolin G increases histone H3 and H4 acetylation at the p21 Waf1/Cip1 promoter. • Upregulation of p21 Waf1/Cip1 is essential for propolin G-induced G1 cell cycle arrest. • Propolin G shows potential as a functional food agent for cancer prevention.