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Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model
Abstract:
Activating transcription factor 3 (ATF3) responds to diverse cellular stresses, and regulates oncogenic activities (for example, proliferation, survival and migration) through direct transcriptional regulation or protein-protein interactions. Although aberrant ATF3 expression is frequently found in human cancers, the role of ATF3 in tumorigenesis is poorly understood. Here, we demonstrate that ATF3 suppresses the development of prostate cancer induced by knockout of the tumor suppressor Pten in mouse prostates. Whereas the oncogenic stress elicited by Pten loss induced ATF3 expression in prostate epithelium, we found that ATF3 deficiency increased cell proliferation and promoted cell survival, leading to early onset of mouse prostatic intraepithelial neoplasia and the progression of prostate lesions to invasive adenocarcinoma. Importantly, the loss of ATF3 promoted activation of the oncogenic AKT signaling evidenced by high levels of phosphorylated AKT and S6 proteins in ATF3-null prostate lesions. In line with these in vivo results, knockdown of ATF3 expression in human prostate cancer cells by single guided RNA-mediated targeting activated AKT and increased matrix metalloproteinase-9 expression. Our results thus link ATF3 to the AKT signaling, and suggest that ATF3 is a tumor suppressor for the major subset of prostate cancers harboring dysfunctional Pten.
Insights
Activating transcription factor 3 (ATF3) acts as a tumor suppressor in prostate cancer. Loss of ATF3 promotes cancer development and progression by activating AKT signaling.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Activating transcription factor 3 (ATF3) responds to cellular stress and influences cancer-related activities.
- Aberrant ATF3 expression is common in human cancers, but its specific role in tumorigenesis remains unclear.
Purpose of the Study:
- To investigate the role of ATF3 in prostate cancer development and progression.
- To elucidate the molecular mechanisms by which ATF3 influences prostate cancer, particularly in the context of Pten loss.
Main Methods:
- Utilized a mouse model with Pten knockout in prostate epithelium to induce oncogenic stress.
- Assessed the impact of ATF3 deficiency on cell proliferation, survival, and tumor progression.
- Analyzed AKT signaling pathway activation via phosphorylated AKT and S6 protein levels.
- Employed single-guide RNA (sgRNA) to knockdown ATF3 in human prostate cancer cells.
Main Results:
- ATF3 deficiency accelerated prostate cancer development and progression in mice with Pten loss.
- Loss of ATF3 led to increased cell proliferation and survival, promoting prostatic intraepithelial neoplasia and invasive adenocarcinoma.
- ATF3 deficiency correlated with enhanced AKT signaling activation and increased matrix metalloproteinase-9 expression in both mouse and human prostate cancer models.
Conclusions:
- ATF3 functions as a tumor suppressor in prostate cancer, particularly in cancers with Pten dysfunction.
- ATF3's tumor-suppressive role is linked to the regulation of AKT signaling.
- These findings suggest ATF3 as a potential therapeutic target for a significant subset of prostate cancers.
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