Abstract 2162: Loss of ATF3 promotes akt activation and prostate cancer development in a pten knockout mouse model

Abstract

Abstract Activating transcription factor 3 (ATF3) responds to diverse cellular stresses, and regulates oncogenic activities (e.g., proliferation, survival and migration) through direct transcriptional regulation or protein-protein interactions. Although aberrant ATF3 expression was often 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 oncogenic stress caused by Pten loss induced ATF3 expression in prostate epithelium, we found that ATF3 deficiency increased cell proliferation but inhibited apoptosis, leading to early onset of mouse prostatic intraepithelial neoplasia and the progression of prostate lesions to invasive adenocarcinoma. Importantly, loss of ATF3 appeared to promote 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 sgRNA-mediated targeting activated AKT, elevated NF-KB nuclear translocation and increased expression of a broad of matrix metalloproteinase such as MMP-9, MMP-10. By zymography and q-PCR assays, we found that MMP-9 expression increased in ATF3-knockdown DU145 and PC3 cells. Also from luciferase reporter result, we further confirmed that loss of ATF3 could elevate MMP-9 expression via activating NF-KB. And in vivo immunochemistry results also show increased MMP9 expression and discontinuous a-SMA staining along prostate glands. These results were well anticipated that ATF3 deficiency leads to activated AKT signaling, which further activates IKK-A to increase nuclear translocation of NF-KB, which in turn binds to the MMP-9 promoter and induces MMP-9 expression in ATF3-downregulated prostate cancer cells, then promotes invasion in Pten-lost mouse prostates. Our results thus link ATF3 to the AKT signaling, and provide the first genetic evidence supporting that ATF3 is a tumor suppressor for a subset of prostate cancers harboring dysfunctional Pten. Citation Format: Ziyan Wang, Dong Xu, Chunhong Yan. Loss of ATF3 promotes akt activation and prostate cancer development in a pten knockout mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2162. doi:10.1158/1538-7445.AM2015-2162