Advanced search
Start date
Betweenand
Related content
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

SET overexpression decreases cell detoxification efficiency: ALDH2 and GSTP1 are downregulated, DDR is impaired and DNA damage accumulates

Full text
Author(s):
Almeida, Luciana O. [1] ; Goto, Renata N. [1] ; Pestana, Cezar R. [2] ; Uyemura, Sergio A. [1] ; Gutkind, Silvio [3] ; Curti, Carlos [2] ; Leopoldino, Andreia M. [1]
Total Authors: 7
Affiliation:
[1] Univ Sao Paulo, Dept Anal Clin Toxicol & Bromatol, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil
[2] Univ Sao Paulo, Dept Quim & Fis, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil
[3] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD - USA
Total Affiliations: 3
Document type: Journal article
Source: FEBS Journal; v. 279, n. 24, p. 4615-4628, DEC 2012.
Web of Science Citations: 12
Abstract

Alcohol and tobacco consumption are risk factors for head and neck squamous cell carcinoma (HNSCC). Aldehyde dehydrogenase 2 (ALDH2) and glutathione Stransferase pi 1 (GSTP1) are important enzymes for cellular detoxification and low efficiencies are implicated in cancer. We assessed the potential role of SET protein overexpression, a histone acetylation modulator accumulated in HNSCC, in gene regulation and protein activity of ALDH2 and GSTP1. SET was knocked down in HN13, HN12 and Cal27, and overexpressed in HEK293 cells; ethanol and cisplatin were the chemical agents. Cells with SET overexpression (HEK293/SET, HN13 and HN12) showed lower ALDH2 and GSTP1 mRNA levels and trichostatin A increased them (real-time PCR). Ethanol upregulated GSTP1 and ALDH2 mRNAs, whereas cisplatin upregulated GSTP1 in HEK293 cells. SET-chromatin binding revealed SET interaction with ALDH2 and GSTP1 promoters, specifically via SET NAP domain; ethanol and cisplatin abolished SET binding. ALDH2 and GSTP1 efficiency was assessed by enzymatic and comet assay. A lower ALDH2 activity was associated with greater DNA damage (tail intensity) in HEK293/SET compared with HEK293 cells, whereas HN13/siSET showed ALDH2 activity higher than HN13 cells. HN13/siSET cells showed increased tail intensity. Cisplatin-induced DNA damage response showed negative relationship between SET overexpression and BRCA2 recruitment. SET downregulated repair genes ATM, BRCA1 and CHEK2 and upregulated TP53. Cisplatin-induced cell-cycle arrest occurred in G0/G1 and S in HEK293 cells, whereas HEK293/SET showed G2/M stalling. Overall, cisplatin was more cytotoxic for HN13 than HN13/siSET cells. Our data suggest a role for SET in cellular detoxification, DNA damage response and genome integrity. (AU)

FAPESP's process: 10/20536-4 - Study of functions of the acidic domain and NAP domain of SET protein in cell line
Grantee:Renata Nishida Goto
Support Opportunities: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 09/52228-0 - Studies on resistance to apoptosis in cancer, head/neck model: signaling via with emphasis on PIP3-Akt/SET, oxidative stress, mitochondria and relationships
Grantee:Carlos Curti
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 09/10783-7 - Molecular study of hnRNP K and SET proteins on transcription and translational proteins associated in oral tumorigenesis
Grantee:Luciana Oliveira de Almeida
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 10/20384-0 - Identification of genes, miRNAs and proteins regulated by set oncoprotein and associated on malignization and tumor progression in HNSCC using in vitro and in vivo models
Grantee:Andréia Machado Leopoldino
Support Opportunities: Regular Research Grants