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cAMP Analogs Induce p53-independent p21 Expression through Sp1-responsive Promoter Activation and p300-associated Epigenetic Regulation in PC-3 Human Prostate Cancer Cells

Year: 2026

Type: article

Abstract: cAMP signaling regulates cell proliferation and survival in various cancers, but the molecular mechanisms underlying its antiproliferative effects in androgen-independent prostate cancer are not fully understood. This study investigated the growth-inhibitory effects of cAMP signaling and its regulatory mechanisms in p53-deficient PC-3 human prostate cancer cells using cAMP analogs, 8-bromo-cAMP and dibutyryl-cAMP. Both cAMP analogs significantly suppressed PC-3 cell proliferation in a time-dependent manner, inducing G1 cell cycle arrest and apoptotic cell death. cAMP treatment reduced cyclin-dependent kinase (Cdk) activity and retinoblastoma protein (pRB) phosphorylation, which enhanced pRB-E2F complex formation and repressed E2F-dependent signaling. cAMP analogs significantly upregulated p21 expression at both transcriptional and translational levels, independently of p53. The increased binding of p21 to Cdk2 and Cdk4 supported its role in inhibiting cyclin-Cdk. Promoter analyses showed that cAMP transcriptionally activated the p21 promoter via Sp1-responsive elements. While the transcription co-activator p300, possessing histone acetyltransferase activity, enhanced cAMP-induced p21 promoter activity, dominant-negative p300 attenuated this effect. Furthermore, trichostatin A, a histone deacetylase inhibitor, potentiated p21 promoter activation, indicating that histone acetylation is crucial for cAMP-mediated p21 transcription. In conclusion, cAMP analogs suppress PC-3 cell proliferation through a mechanism involving p53-independent p21 induction, together with Sp1-responsive promoter activation and p300-associated epigenetic regulation.

Source: Journal of Cancer Prevention

DOI: 10.15430/jcp.26.031

Authors: Hyun Hwangbo, Sung Ok Kim, Soon-Jeong Jeong, Su Hyun Hong, Yung Hyun Choi

Institutions: Dong-Eui University, Kyungsung University, Youngsan University

Language: English

Topic: Prostate Cancer Treatment and Research

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: diamond

Funders: National Research Foundation, National Research Foundation of Korea, National Institutes of Health