Abstract
Endometrial cancer remains to be a major type of malignancy in threatening female life. Molecular insights in advancing our understanding of endometrial tumorigenesis are much needed. We here report that a less-studied protein Dihydropyrimidinase like 3 (DPYSL3) is a potent tumor suppressor. DPYSL3 is uniquely regulated by wild type p53 (wtp53), and its expression is at the highest level when cells carry wtp53 and are exposed to hypoxia. We reveal that wtp53 can bind DPYSL3 promoter to enhance DPYSL3 expression and in turn, the elevated DPYSL3 can restrain cancer cell proliferation and invasion in vitro and in vivo. Importantly, we observe that DPYSL3 can interfere with MAP kinase pathway, supported by a substantially reduced level of phosphorylated ERK in cells with high expression of DPYSL3. Furthermore, we identify the specific region of DPYSL3 that is responsible for its interaction with MEK and a subsequently reduced activity of ERK. In combination of molecular docking and mutagenesis analysis, we validated that the therapeutic implication of 17 A.A.s of DPYSL3, which can reduce the activity of the MAPK pathway and inhibit endometrial tumor cell growth in vitro and in vivo. Therefore, our study not only demonstrates in-depth understanding of human tumorigenesis, especially endometrial tumor, but also only provides a therapeutic potential to develop an effective tool to fight against human malignancy.
Highlights
Endometrial cancer (EC) as one of the most common type of malignancy in female exhibits a rapid growth of morbidity around the world in recent years (Wright, 2016)
Hypoxia stimulates Dihydropyrimidinase like 3 (DPYSL3) up-regulation in EC cell lines with wild type p53 To validate the presence of DPYSL3 up-regulation by p53 over-expression in our previous RNA sequencing data, DPYSL3 mRNA and protein level were examined in EC cells of COLO-684 and HEC-108 as well as Ishikawa and HEC-59 treated with a hypoxia-mimic drug deferoxamine (DFO) or 5-fluorouracil (5-FU) known to damage DNA
The higher expression of DPYSL3 was observed after DFO or 5-FU exposure compared to non-treatment both in COLO-684 but not in Ishikawa cells (Figs. 1A–1D), which indicated that DPYSL3 was induced in a wild type p53-regulated manner under hypoxic stress and DNA damage condition
Summary
Endometrial cancer (EC) as one of the most common type of malignancy in female exhibits a rapid growth of morbidity around the world in recent years (Wright, 2016). In the majority of type I cases, patients are often diagnosed at an early stage, and can be well healed under the standard surgical treatment and following chemotherapy (82% for 5-year disease free survival) (Bregar et al, 2017; Francis et al, 2019). Those relapsed patients fail to get satisfactory therapeutic effect and show the poor prognosis due to malignant proliferation and distant metastasis (Connor and Rose, 2018; Polcher et al, 2019).
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