Abstract
Prostate cancer (PCa) is a leading cause of cancer-related death in men, with its progression and treatment response being complex. The study focuses on the role of HIC1 (Hypermethylated in cancer 1) in PCa, revealing its downregulation in PCa tissues compared to normal counterparts. Using transcriptome sequencing and bioinformatics, it was found that HIC1 influences key cellular processes like cell growth, proliferation, invasion, and androgen receptor (AR) signaling in PCa. Specifically, AR was identified as a transcription factor for insulin receptor substrate 2 (IRS2), which activates the PI3K/AKT pathway, enhancing PCa cell proliferation and invasion. However, this effect could be reversed by IRS2 inhibition using NT157. Furthermore, HIC1 overexpression reduced castration resistance in PCa cells, with in vivo studies showing that HIC1 silencing increased PCa xenograft growth and resistance, and elevated Ki-67, Cleaved-caspase-3, EMT markers, and prostate-specific antigen (PSA) levels. Conversely, AR and IRS2 inhibitors like EPI-7170 and NT157 negatively affected PCa progression. These results underscore HIC1's potential as a therapeutic target in PCa, offering new insights into its role in cancer biology and treatment.
Keywords:
HIC1; IRS2; PI3K/AKT axis; androgen receptor; castration resistance; prostate cancer.