P53 functional states are associated with distinct aldehyde dehydrogenase transcriptomic signatures

Shanying Gui,Wendi Q O’Neill,Quintin Pan,Kate Chatfield-Reed,Jun-Ge Yu,Theodoros N Teknos,Xiujie Xie

doi:10.1038/s41598-020-57758-5

Abstract

p53 and aldehyde dehydrogenase (ALDH) have been implicated in key tumorigenesis processes including cancer initiating cell (CIC) maintenance; however, the relationship between these two mediators remains poorly defined. In this study, ALDH isoform expression diversity was revealed in CICs with disparate p53 functional states: gain of function, high risk p53 mutation (p53HRmut) and wildtype p53 (p53WT) inactivated by the human papillomavirus 16 (HPV16) E6 oncogene. Interrogation of head and neck squamous cell carcinoma (HNSCC) cell lines and patient tumors showed that HPV16+/p53WT cases have higher ALDH variance score (AVS), a measure of tumor ALDH isoform expression diversity, compared to HPV−/p53HRmut cases (p = 0.03). AVS and several individual ALDH isoforms were associated with prognosis in HPV16+/p53WT HNSCC but not in HPV−/p53HRmut HNSCC. Knockdown of the dominant ALDH isoform in high AVS HNSCC depleted the CIC pool in vitro and in vivo. Our results demonstrate that p53 functional states are associated with distinct ALDH isoform transcriptomic signatures. Moreover, tumor ALDH profiling may provide insight on which ALDH isoform to target in high AVS HNSCC tumors to deplete the CIC population.

Highlights

P53 and aldehyde dehydrogenase (ALDH) have been implicated in key tumorigenesis processes including cancer initiating cell (CIC) maintenance; the relationship between these two mediators remains poorly defined
Our work demonstrates that p53 functional states are associated with distinct ALDH isoform transcriptomic signatures and suggests that tumor ALDH profiling may identify the isoform responsible for CIC maintenance in high ALDH variance score (AVS) head and neck squamous cell carcinoma (HNSCC)
human papillomavirus 16 (HPV16)+ HNSCC cell lines, UD-SCC2, UMSCC47, and UPCI-SCC090, have wildtype p53 that is inactivated by HPV16E617

Summary

Introduction

P53 and aldehyde dehydrogenase (ALDH) have been implicated in key tumorigenesis processes including cancer initiating cell (CIC) maintenance; the relationship between these two mediators remains poorly defined. ALDH isoform expression diversity was revealed in CICs with disparate p53 functional states: gain of function, high risk p53 mutation (p53HRmut) and wildtype p53 (p53WT) inactivated by the human papillomavirus 16 (HPV16) E6 oncogene. Interrogation of head and neck squamous cell carcinoma (HNSCC) cell lines and patient tumors showed that HPV16+/p53WT cases have higher ALDH variance score (AVS), a measure of tumor ALDH isoform expression diversity, compared to HPV−/p53HRmut cases (p = 0.03). Head and neck squamous cell carcinomas (HNSCCs) are cancers from various anatomical site in the head and neck region and can be subdivided based on two major etiologic factors: smoking/alcohol use and high-risk human papillomavirus (HPV), in particular HPV16. Our work demonstrates that p53 functional states are associated with distinct ALDH isoform transcriptomic signatures and suggests that tumor ALDH profiling may identify the isoform responsible for CIC maintenance in high AVS HNSCC

Methods

Results

Conclusion