Blocking eIF5A modification in cervical cancer cells alters the expression of cancer-related genes and suppresses cell proliferation.
Cancer etiology is influenced by alterations in protein synthesis that are not fully understood. In this study, we took a novel approach to investigate the role of the eukaryotic translation initiation factor eIF5A in human cervical cancers, where it is widely overexpressed. eIF5A contains the distinctive amino acid hypusine, which is formed by a posttranslational modification event requiring deoxyhypusine hydroxylase (DOHH), an enzyme that can be inhibited by the drugs ciclopirox and deferiprone. We found that proliferation of cervical cancer cells can be blocked by DOHH inhibition with either of these pharmacologic agents, as well as by RNA interference-mediated silencing of eIF5A, DOHH, or another enzyme in the hypusine pathway. Proteomic and RNA analyses in HeLa cervical cancer cells identified two groups of proteins in addition to eIF5A that were coordinately affected by ciclopirox and deferiprone. Group 1 proteins (Hsp27, NM23, and DJ-1) were downregulated at the translational level, whereas group 2 proteins (TrpRS and PRDX2) were upregulated at the mRNA level. Further investigations confirmed that eIF5A and DOHH are required for Hsp27 expression in cervical cancer cells and for regulation of its key target IκB and hence NF-κB. Our results argue that mature eIF5A controls a translational network of cancer-driving genes, termed the eIF5A regulon, at the levels of mRNA abundance and translation. In coordinating cell proliferation, the eIF5A regulon can be modulated by drugs such as ciclopirox or deferiprone, which might be repositioned to control cancer cell growth.
Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Pathology and Laboratory Medicine, Obstetrics, Gynecology and Women's Health, and Medicine, New Jersey Medical School, Rutgers University, Newark, New Jersey.
Elisabeth
E
Mémin
Mainul
M
Hoque
Mohit R
MR
Jain
Debra S
DS
Heller
Hong
H
Li
Bernadette
B
Cracchiolo
Hartmut M
HM
Hanauske-Abel
Tsafi
T
Pe'ery
Michael B
MB
Mathews
D000935:Antifungal Agents / Q000494:pharmacology; D049109:Cell Proliferation; D000077768:Ciclopirox; D000077543:Deferiprone; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D040901:Proteomics / Q000379:methods; D011728:Pyridones / Q000494:pharmacology; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*; D000097574:Eukaryotic Translation Initiation Factor 5A
D000935:Antifungal Agents; D000077768:Ciclopirox; D000077543:Deferiprone; D007502:Iron Chelating Agents; D006899:Mixed Function Oxygenases; D016328:NF-kappa B; D010448:Peptide Initiation Factors; D011728:Pyridones; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C047991:deoxyhypusine hydroxylase