Evaluation of the Role of p53 Tumour Suppressor Posttranslational Modifications and TTC5 Cofactor in Lung Cancer.

Hasen Alhebshi,Patricia Anthonia Johanna Muller,Kun Tian,Marija Krstic-Demonacos,Delta Patricia Menendez Creamer,Luciano Mutti,Nazila Safari,Lipsita Patnaik,Constantinos Demonacos,Rebecca Taylor,Mohamad Nidal Bittar,Pavel Bezecny,Callum Hall

doi:10.3390/ijms222413198

Abstract

Mutations in the p53 tumor suppressor are found in over 50% of cancers. p53 function is controlled through posttranslational modifications and cofactor interactions. In this study, we investigated the posttranslationally modified p53, including p53 acetylated at lysine 382 (K382), p53 phosphorylated at serine 46 (S46), and the p53 cofactor TTC5/STRAP (Tetratricopeptide repeat domain 5/ Stress-responsive activator of p300-TTC5) proteins in lung cancer. Immunohistochemical (IHC) analysis of lung cancer tissues from 250 patients was carried out and the results were correlated with clinicopathological features. Significant associations between total or modified p53 with a higher grade of the tumour and shorter overall survival (OS) probability were detected, suggesting that mutant and/or modified p53 acts as an oncoprotein in these patients. Acetylated at K382 p53 was predominantly nuclear in some samples and cytoplasmic in others. The localization of the K382 acetylated p53 was significantly associated with the gender and grade of the disease. The TTC5 protein levels were significantly associated with the grade, tumor size, and node involvement in a complex manner. SIRT1 expression was evaluated in 50 lung cancer patients and significant positive correlation was found with p53 S46 intensity, whereas negative TTC5 staining was associated with SIRT1 expression. Furthermore, p53 protein levels showed positive association with poor OS, whereas TTC5 protein levels showed positive association with better OS outcome. Overall, our results indicate that an analysis of p53 modified versions together with TTC5 expression, upon testing on a larger sample size of patients, could serve as useful prognostic factors or drug targets for lung cancer treatment.

Highlights

Lung cancer is a common type of cancer as well as a frequent cause of death in both men and women worldwide
Since IHC results indicated that the acetylated form of p53 at lysine 382 in some tissue samples from lung cancer patients was detected in the cytoplasm, the expression of this isoform was analysed in cancer cell lines using the immunofluorescence technique
In A549 and U2OS cells, the TTC5 protein was observed in both the nucleus and cytoplasm (Supplementary Figure S6). These results suggest that the acetylated p53 was expressed generally in the nucleus, whereas the TTC5 protein was expressed in the nucleus and the cytoplasm in cell lines investigated

Summary

Introduction

Lung cancer is a common type of cancer as well as a frequent cause of death in both men and women worldwide. In the UK in 2017, lung cancer was the third most common cancer More than a million new cases of lung cancer are diagnosed worldwide [1]. Lung cancer can be categorized into two types depending on its histological appearance. These types are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Most patients are diagnosed at the stage of advanced disease and despite continued improvement in therapy, the five-year survival rate remains low [4,5]

Methods

Results

Conclusion