Abstract
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.
Original language | English |
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Article number | P119 |
Number of pages | 1 |
Journal | Endocrine Abstracts |
Volume | 59 |
DOIs | |
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 https://www.endocrinology.org/events/sfe-bes-conference/sfe-bes-2018/ |