PSAT1 is regulated by ATF4 and enhances cell proliferation via the GSK3β/β-catenin/cyclin D1 signaling pathway in ER-negative breast cancer

Abstract

BackgroundA growing amount of evidence has indicated that PSAT1 is an oncogene that plays an important role in cancer progression and metastasis. In this study, we explored the expression and function of PSAT1 in estrogen receptor (ER)-negative breast cancer.MethodThe expression level of PSAT1 in breast cancer tissues and cells was analyzed using real-time-PCR (RT-PCR), TCGA datasets or immunohistochemistry (IHC). The overall survival of patients with ER-negative breast cancer stratified by the PSAT1 expression levels was evaluated using Kaplan-Meier analysis. The function of PSAT1 was analyzed using a series of in vitro assays. Moreover, a nude mouse model was used to evaluate the function of PSAT1 in vivo. qRT-PCR and western blot assays were used to evaluate gene and protein expression, respectively, in the indicated cells. In addition, we demonstrated that PSAT1 was activated by ATF4 by chromatin immunoprecipitation (ChIP) assays.ResultsmRNA expression of PSAT1 was up-regulated in ER-negative breast cancer. A tissue microarray that included 297 specimens of ER-negative breast cancer was subjected to an immunohistochemistry assay, which demonstrated that PSAT1 was overexpressed and predicted a poor clinical outcome of patients with this disease. Our data showed that PSAT1 promoted cell proliferation and tumorigenesis in vitro and in vivo. We further found that PSAT1 induced up-regulation of cyclin D1 via the GSK3β/β-catenin pathway, which eventually led to the acceleration of cell cycle progression. Furthermore, ATF4 was also overexpressed in ER-negative breast cancers, and a positive correlation between the ATF4 and PSAT1 mRNA levels was observed in ER-negative breast cancers. We further demonstrated that knockdown of ATF4 by siRNA reduced PSAT1 expression. Finally, chromatin immunoprecipitation (ChIP) assays showed that PSAT1 was a target of ATF4.ConclusionsPSAT1, which is overexpressed in ER-negative breast cancers, is activated by ATF4 and promotes cell cycle progression via regulation of the GSK3β/β-catenin/cyclin D1 pathway.Electronic supplementary materialThe online version of this article (doi: 10.1186/s13046-017-0648-4) contains supplementary material, which is available to authorized users.

The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism

“…Indeed, our gene expression analysis indicated that the IKKε-mediated pathway defines a subset of ER -, basal breast tumours, thus evaluation of the IKKε-mediated metabolic and gene expression phenotype can help to further stratify breast cancer for treatment. While more investigation is required to elucidate the functional consequence of IKKe-induced PSAT1 phosphorylation, analysis of the recent phospho-proteomic dataset of breast cancer (Mertins et al, 2016) also indicated that PSAT1 phosphorylation is associated with triple negative, basal type (see Table 3), and our stratification is also in agreement with previous studies, where strong correlation between PSAT1 expression and tumour proliferation has been found in ERtumours (Coloff et al, 2016;Gao et al, 2017). Of note, IKKε, along with the JAK/STAT pathway, has been reported to regulate a cytokine network promoting cellular proliferation in a subset of triple negative breast tumours (Barbie et al, 2014), and PSAT1 overexpression is also a feature of a small fraction of ER + tumours along with the JAK-STAT pathway (De Marchi et al, 2017).…”

“…7D-H). ATF4 driven overexpression of PSAT1 in ER negative tumours has been previously shown in a different dataset (Gao et al, 2017) and here we also have found strong association of these two genes (Fig. 7I, J).…”

Molecular targets of curcumin in breast cancer (Review)

“…Overexpression of β-catenin leads to constitutive activation of cell proliferation (68), and tumor cells downregulate the tumor suppressor GSK3β, which limits the activity of β-catenin by triggering its ubiquitin-mediated proteosomal degradation. Therefore, targeting the Wnt/β-catenin signaling pathway is an attractive approach in cancer therapy (69,70).…”

Network analysis allows to unravel breast cancer molecular features and to identify novel targets

“…PSAT1 is the second enzyme in the serine biosynthesis pathway, important for the generation of many cell building blocks (Antonov, Agostini, Morello, & Minieri, 2014;Deberardinis, 2011;Possemato et al, 2011). Several enzymes involved in serine biosynthesis, such as SHMT2 and PHGDH, have been correlated with negative prognosis in BC (Antonov et al, 2014), and PSAT1 itself has been shown to induce proliferation in basal-like BC cell lines (Gao et al, 2017;Marchi et al, 2017). Interestingly, the PSAT1 gene appears to be regulated by FOXC1, a central hub of the same KRAS_dn1 module and associated with BC development (GSE73234, Han et al, 2017).…”