The proto‐oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer

Abstract

The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xenograft models. However, the precise role of PBF in tumorigenesis and its prognostic value as a cancer biomarker remain largely uncharacterised, particularly in malignancies outside the thyroid. Here, we provide the first evidence that PBF represents a promising prognostic marker in colorectal cancer. Examination of a total of 39 patients demonstrated higher PBF expression at both the mRNA (P ¼ 0.009) and protein (P < 0.0001) level in colorectal tumors compared to matched normal tissue. Critically, PBF was most abundant in colorectal tumors associated with Extramural Vascular Invasion (EMVI), increased genetic instability (GI) and somatic TP53 mutations, all features linked with recurrence and poorer patient survival. We further demonstrate by glutathione-S-transferase (GST) pull-down and coimmunoprecipitation that PBF binds to the tumor suppressor protein p53, as well as to p53 mutants (D126-132, M133K, V197E, G245D, I255F and R273C) identified in the colorectal tumors. Importantly, overexpression of PBF in colorectal HCT116 cells interfered with the transcriptional activity of p53-responsive genes such as mdm2, p21 and sfn. Diminished p53 stability (> 90%; P < 0.01) was also evident with a concurrent increase in ubiquitinated p53. Human colorectal tumors with wild-type TP53 and high PBF expression also had low p53 protein levels (P < 0.05), further emphasizing a putative interaction between these genes in vivo. Overall, these results demonstrate an emerging role for PBF in colorectal tumorigenesis through regulating p53 activity, with implications for PBF as a prognostic indicator for invasive tumors.

Pro-invasive Effect of Proto-oncogene PBF Is Modulated by an Interaction with Cortactin

“…The precise role of PBF in tumor cell invasion remains poorly understood in breast, thyroid, and colorectal cancer cells (15–18). We therefore sought to investigate the ability of PBF to induce invasion across a panel of cancer cells (Supplemental Table 1).…”

“…Secondly, high PBF promoter activity was associated with poorer clinical outcome and increased metastatic risk in breast cancer (17). Thirdly, colorectal tumors with higher PBF protein expression demonstrated greater vascular invasion (18). Thus, it is possible that PBF is integral to tumor cell invasion in vivo.…”

“…Its best described role however lies in binding the sodium iodide symporter NIS and regulating its subcellular localization within thyroid cells (20, 21). PBF also interacts with the tumor suppressor p53 (18, 22) and the protein kinase Src (23). In particular, PBF is a phospho-protein and interaction with Src elicits phosphorylation at tyrosine (Y) residue 174.…”

Iodide transport and breast cancer

“…colorectal (McCabe et al 2003, Stratford et al 2005, Watkins et al 2010, Read et al 2014. PBF has been reported to repress radioiodide uptake in thyroid cancer cells by binding to NIS, which leads to NIS internalisation and inhibition of function (Smith et al 2009).…”

WOMEN IN CANCER PROFILE: From bedside to bench and back: my journey in thyroid disease

“…It soon became apparent that PTTG and PBF are involved in other endocrine tumours, and I identified that overexpression of PTTG and PBF are markers of prognosis in thyroid cancer, independent of patients' age and gender and of tumour type and size (Boelaert et al 2003a, Stratford et al 2005. Subsequent studies in our group have confirmed overexpression in other endocrine-related neoplasia including colon (Read et al 2016) and breast cancers (Boelaert & Franklyn 2003, Watkins et al 2010. Further functional investigations have unravelled some of the mechanisms through which these genes signal indicating roles in the initiation (Kim et al 2005) as well as the promotion of tumourigenesis through the upregulation of pro-mitogenic and pro-angiogenic growth factors (Kim et al 2006a,b).…”