Tumor Suppressor Function of ATF3 in Prostate Cancer

It has long been established that genetic alterations leading to down-regulated expression of the tumor suppressor protein Pten characterize a major subtype of prostate cancer. As reported recently in Oncogene, the laboratory of GRU Cancer Center’s Dr. Chunhong Yan – including Cancer Center researchers Drs. Ziyan Wang and Han-Fei Ding and colleagues – demonstrates that yet another protein, ATF3 (activating transcription factor 3), functions as a tumor suppressor when Pten is compromised. Their study used ∆ATF3, ∆Pten, and ∆ATF3∆Pten mouse models on the black C57BL/6 background to knock out the expression of ATF3, Pten, or both from mouse prostates. ATF3 is known to be activated upon oncogenic stress, and the Yan group confirmed that ATF3 expression in prostate epithelium initially increased with Pten loss, although its expression fell as the lesions progressed. In the double knock-outs, prostate cancer was found to be more invasive and to progress more rapidly compared to ∆Pten counterparts: By six weeks of age, 91% (10 of 11) ∆ATF3∆Pten versus 44% (4 of 9) ∆Pten mice developed prostatic intraepithelial neoplasm, and by 9 weeks, 89% (8 of 9) ∆ATF3∆Pten versus 36% (4 of 11) ∆Pten mice developed adenocarcinoma. Further studies indicated that AFT3 loss conferred increased proliferation and decreased apoptosis to Pten loss-induced prostate carcinogenesis. The researchers went on to demonstrate both in vivo and in vitro (using CRISPR-Cas9-based technology in several human prostate cancer cell lines) that as with knockdown of Pten, knockdown of ATF3 activates AKT phosphorylation, which is associated with cell proliferation, survival, and invasion. Further mechanistic studies demonstrate that AKT activation induced by ATF3 loss leads to NF-kB signaling, resulting in increased MMP-9 expression, which the authors attribute to the increased invasion observed in ∆ATF3∆Pten tumors.

[Wang Z, Xu D, Ding H-F, Kim J, Zhang J, Hai T, Yan C. Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model. Oncogene. 2015 Sep 17;34(38):4975-84.]
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Written by Allison Brown

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