PIR promotes tumorigenesis of breast cancer by upregulating cell cycle activator E2F1

Abstract

Pirin (PIR) protein belongs to the superfamily of cupin and is highly conserved between eukaryotic and prokaryotic organisms. It has been reported that PIR is upregulated in various tumors and involved in tumorigenesis. However, its biological functions particularly in promoting tumorigenesis are, to date, poorly characterized. Here we report that knockdown of PIR in MCF7 and MDA-MB-231 cell lines causes a dramatic decrease in cell proliferation and xenograft tumor growth in mice. Mechanistically, the cell cycle activator E2F1 and its target genes cdk4, cdk6, cycE, cycD and DDR1 are remarkably downregulated in PIR depleted cells, leading to G1/S phase arrest. Luciferase reporter assay and chromatin immunoprecipitation assay indicate that PIR can activate E2F1 transcription by binding to its promoter region. Consistent with the observation in PIR knockdown cells, PIR inhibitors markedly inhibit the proliferation of both cell lines. Furthermore, knockdown of PIR significantly decreases the abilities of MCF7 cells for mobility and invasion in vitro and their metastasis in mice, which may be attributed to the decrease of DDR1. In conclusion, PIR stimulates tumorigenesis and progression by activating E2F1 and its target genes. Our finding thus suggests PIR as a potential druggable target for the therapy of cancers with high expression level of PIR.

Role of Pirin, an Oxidative Stress Sensor Protein, in Epithelial Carcinogenesis

“…Nevertheless, Pirin levels are highly correlated with positive axillary lymph nodes status, suggesting a connection between high Pirin levels and local metastasis [ 88 ]. Furthermore, PIR knockdown resulted in a noticeably reduced cell proliferation rate in breast cancer cells and decreased xenograft tumor growth in mice [ 89 ]. In addition, Pirin mediates breast tumorigenesis by promoting E2F1 expression, a key cell cycle regulator that is abnormally active in malignant tumors [ 89 , 90 , 91 ].…”

“…Furthermore, PIR knockdown resulted in a noticeably reduced cell proliferation rate in breast cancer cells and decreased xenograft tumor growth in mice [ 89 ]. In addition, Pirin mediates breast tumorigenesis by promoting E2F1 expression, a key cell cycle regulator that is abnormally active in malignant tumors [ 89 , 90 , 91 ]. In fact, Pirin binds to the 3′-terminal region of the E2F1 promoter and subsequently facilitates G1 to S phase transition in breast cancer cells [ 89 ].…”

Role of Pirin, an Oxidative Stress Sensor Protein, in Epithelial Carcinogenesis

“…Nevertheless, Pirin levels are highly correlated with positive axillary lymph nodes status, suggesting a connection between high Pirin levels and local metastasis [76]. On the other hand, PIR knockdown resulted in a noticeably reduced cell proliferation rate in breast cancer cells and a decreased xenograft tumor growth in mice [77]. In addition, Pirin mediates breast tumorigenesis by promoting E2F1 expression, a key cell cycle regulator that is abnormally active in malignant tumors [77][78][79].…”

“…On the other hand, PIR knockdown resulted in a noticeably reduced cell proliferation rate in breast cancer cells and a decreased xenograft tumor growth in mice [77]. In addition, Pirin mediates breast tumorigenesis by promoting E2F1 expression, a key cell cycle regulator that is abnormally active in malignant tumors [77][78][79]. In fact, Pirin binds to the 3′-terminal region of E2F1 promoter and subsequently facilitates G1 to S phase transition in breast cancer cells [77].…”

Mutational Landscape of Pirin and Elucidation of the Impact of Most Detrimental Missense Variants That Accelerate the Breast Cancer Pathways: A Computational Modelling Study

“…Previous studies reported the overexpression of PIR in different neoplastic transformation and its role in the enhancement of tumor formation due to inducing the expression of Bcl3 by forming the ternary complex with proto-oncogenes Bcl3 and NF-kB ( Zhu et al, 2003 ; Massoumi et al, 2009 ). Recently, it has been identified that PIR positively regulates breast cancer cell proliferation, xenograft tumor formation, and metastasis, through an enforced transition of G1/S phase of the cell cycle by upregulation of E2F1 expression at the transcriptional level ( Suleman et al, 2019 ). It was a significant breakthrough in unveiling the hidden function of PIR in the field of cancer.…”