Oncogenic action of pituitary-tumor transforming gene (PBF) in head and neck cancer is associated with poorer overall survival
Research output: Contribution to journal › Abstract
Colleges, School and Institutes
PBF is a multifunctional proto-oncogene overexpressed in thyroid and other endocrine cancers. Previously we identified a functional interaction between PBF and the tumour suppressor p53 in well-differentiated thyroid cancer (WDTC). Here, we delineate the oncogenic mechanisms of PBF, along with its binding partner PTTG, in head and neck cancer (HNSCC), in which TP53 mutations (mutTP53) are common (>50%). HNSCC tissue revealed significant upregulation of PBF and PTTG mRNA (>1.6-fold), which was consistent with a TCGA cohort (n=520). Importantly, a panel of 129 p53-target genes showed a more significant correlation with PBF (P=0.0006) and PTTG (P=5.9×10−9) expression in TCGA than the background transcriptome (n=19,764 genes), supporting a functional relationship. In agreement, there were significant mRNA changes in PBF- and PTTG-depleted HNSCC cells for key p53-responsive genes such as BCL2. Co-immunoprecipitation studies confirmed that PBF and PTTG are specific interactors of p53 in HNSCC. PTTG retained the ability to bind p53 in the absence of PBF, but the degree of interaction was significantly attenuated (4-fold) suggesting that PBF facilitates binding of PTTG to p53. Half-life studies showed that PBF and PTTG inhibit p53 stability, with joint over-expression giving the most pronounced decrease (~13-fold). HNSCC TCGA patients with mutTP53 and high PBF/PTTG showed poorer overall survival (median=28.98 months) than those with low PBF/PTTG (median=71.16 months). A significant increase in the incidence of metastatic disease was further evident for wtTP53 HNSCC with high PBF/PTTG expression. In summary, our results indicate that PBF and PTTG functional interaction is not confined to endocrine cancers. HNSCC patients with high tumoural PBF/PTTG have worse outcomes due in part to greater aberration of p53-dependent signalling. These findings may be of relevance to poorly differentiated or anaplastic thyroid cancers which have a higher incidence of TP53 alterations than WDTC.
|Number of pages||1|
|Publication status||Published - 1 Nov 2018|
|Event||Society for Endocrinology BES 2018 - Scottish Event Campus (SEC), Glasgow, United Kingdom|
Duration: 19 Nov 2018 → 21 Nov 2018