Tumor-suppression function of transcription factor USF2 in prostate carcinogenesis

Abstract

Although the transcription factor USF2 has been implicated in the regulation of cellular growth and proliferation, it is unknown whether alterations in USF2 contribute to tumorigenesis and tumor development. We examined the role of USF2 in prostate tumorigenesis. Western blot analysis revealed markedly decreased USF2 levels in three androgen-independent prostate cancer cell lines, PC-3, DU145, and M12, as compared to nontumorigenic prostate epithelial cells or the androgen-dependent cell line, LNCaP. Ectopic expression of USF2 in PC-3 cells did not affect the cell proliferation rate of PC-3 cells on plastic surfaces. However, it dramatically decreased anchorage-independent growth of PC-3 cells in soft agar (90-98% inhibition) and the invasion capability (80% inhibition) of PC-3 cells in matrix gel assay. Importantly, expression of USF2 in PC-3 cells inhibited the tumorigenicity of PC-3 cells in an in vivo nude mice xenograft model (80-90% inhibition). These results suggest that USF2 has tumor-suppression function. Consistent with its function in tumor suppression, we found that the USF2 protein is present in normal prostate epithelial cells but absent in 18 of 42 (43%) human prostate cancer tissues (P = 0.015). To further examine the functional role of USF2 in vivo, we generated mice with genetic deletion of USF2 gene. We found that USF2-null mice displayed marked prostate hyperplasia at a young age, suggesting that USF2 is involved in the normal growth and differentiation of prostate. Together, these studies demonstrate that USF2 has tumor-suppressor function and plays a role in prostate carcinogenesis.

GSK3β-Dependent Phosphorylation Alters DNA Binding, Transactivity and Half-Life of the Transcription Factor USF2

“…At the same time an increased expression of the USF2 target genes FAS, HO-1, and PAI-1 is initiated. This type of regulation, together with the findings of the migration assay is in line with previous reports indicating that GSK3β and USF2 have a role in cancerogenesis [8], [73].…”

“…While a number of studies support the idea of GSK3β being tumor suppressive, others studies showed that GSK3β may promote cancer development [72]. Similar findings were obtained with respect to USF2; being tumor suppressive with respect to prostate cancer [8], [73] but being rather promoting in the development of lung cancer [74] and thyroid cancer [75]. Although no study has yet correlated the activity of GSK3β with the activity of USF2 in a certain tumor setting, the findings of the present study would favor the tumor promoting aspects of GSK3β and USF2 since GSK3β activated USF2 enhanced cell migration which may be important in terms of tumor cell metastasis.…”

“…Furthermore, USF2 seems to be linked to the development of cancer. While several studies indicated a tumor-suppressive function of USF2 in prostate cancer [8], breast cancer [9] and oral cancer [10], a pro-proliferative function of USF2 was observed in lung cancer cells [11].…”

“…GSK3β is an unusual kinase since it is active under resting conditions and is inhibited both by a PKB (AKT) activating growth factor or a Wnt signal [25]. GSK3β appears to be an attractive candidate kinase for the regulation of USF2 since both proteins seem to be involved in the development of different types of cancer, especially prostate cancer [8], [26], [27]. In addition, we found that parts of the USF2 protein sequence match with the substrate recognition preferences of GSK3β [28].…”

Opposite Expression of the Antioxidant Heme Oxygenase-1 in Primary Cells and Tumor Cells: Regulation by Interaction of USF-2 and Fra-1

“…Indeed, inactivation of USF-2 in knockout mice led to the generation of prostate adenomas (9). In addition, USF-2 was found to be completely inactive in several cell lines from breast tumors (23).…”