A novel function of HRP‐3 in regulating cell cycle progression via the HDAC–E2F1–Cyclin E pathway in lung cancer

To improve the poor survival rate of lung cancer patients, we investigated the role of HDGF‐related protein 3 (HRP‐3) as a potential biomarker for lung cancer. The expression of endogenous HRP‐3 in human lung cancer tissues and xenograft tumor models is indicative of its clinical relevance in lung cancer. Additionally, we demonstrated that HRP‐3 directly binds to the E2F1 promoter on chromatin. Interestingly, HRP‐3 depletion in A549 cells impedes the binding of HRP‐3 to the E2F1 promoter; this in turn hampers the interaction between Histone H3/H4 and HDAC1/2 on the E2F1 promoter, while concomitantly inducing Histone H3/H4 acetylation around the E2F1 promoter. The enhanced Histone H3/H4 acetylation on the E2F1 promoter through HRP‐3 depletion increases the transcription level of E2F1. Furthermore, the increased E2F1 transcription levels lead to the enhanced transcription of Cyclin E, known as the E2F1‐responsive gene, thus inducing S‐phase accumulation. Therefore, our study provides evidence for the utility of HRP‐3 as a biomarker for the prognosis and treatment of lung cancer. Furthermore, we delineated the capacity of HRP‐3 to regulate the E2F1 transcription level via histone deacetylation.
HRP‐3 depletion–mediated S‐phase accumulation augments E2F1 transcription. HRP‐3 depletion induces H3/H4 acetylation and obstructs HRP‐3 binding to the E2F1 promoter. The reduction of HDAC 1/2 recruitment in the E2F1 promoter by HRP‐3 depletion increases H3/H4 acetylation in the E2F1 promoter.