Emerging role of HIC1 in prostate cancer progression and therapeutic response: A novel perspective

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Prostate cancer (PCa) remains a significant cause of cancer-related mortality in men.
• The complex mechanisms governing PCa progression and treatment response necessitate further investigation.
• The role of the Hypermethylated in cancer 1 (HIC1) gene in PCa pathogenesis is not fully elucidated.

Purpose of the Study:

• To investigate the functional role of HIC1 in prostate cancer.
• To identify the molecular pathways influenced by HIC1 in PCa.
• To evaluate the therapeutic potential of targeting HIC1 in PCa.

Main Methods:

• Transcriptome sequencing and bioinformatics analysis were employed to identify HIC1's molecular targets and pathways.
• In vitro cell culture models were used to study the effects of HIC1 modulation on PCa cell behavior.
• In vivo xenograft models were utilized to assess the impact of HIC1 on tumor growth and castration resistance.

Main Results:

• HIC1 was found to be significantly downregulated in PCa tissues compared to normal tissues.
• HIC1 influences key cellular processes including proliferation, invasion, and androgen receptor (AR) signaling.
• AR signaling, via insulin receptor substrate 2 (IRS2) and the PI3K/AKT pathway, promotes PCa cell proliferation and invasion, effects reversible by IRS2 inhibition.
• HIC1 overexpression reduced castration resistance, while HIC1 silencing increased tumor growth, resistance, and PSA levels in vivo.
• Inhibitors of AR and IRS2 (EPI-7170, NT157) demonstrated anti-prostate cancer effects.

Conclusions:

• HIC1 plays a critical role in regulating prostate cancer progression and response to therapy.
• HIC1 acts as a tumor suppressor in PCa, influencing AR signaling and cellular proliferation.
• HIC1 represents a promising therapeutic target for prostate cancer treatment, potentially overcoming castration resistance.