The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation.
Cell Cycle
/ physiology
Cell Cycle Proteins
/ genetics
Cell Line, Tumor
Cyclin D1
/ biosynthesis
Disease Progression
E2F2 Transcription Factor
/ genetics
Gene Expression Regulation, Neoplastic
Humans
Mutation
Neoplasms
/ genetics
Promoter Regions, Genetic
Protein Array Analysis
Proto-Oncogene Protein c-fli-1
/ biosynthesis
Telomerase
/ genetics
FLI1
cancer
cell cycle
hTERT
transcription factor
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 07 2020
01 07 2020
Historique:
received:
22
05
2019
revised:
15
11
2019
accepted:
29
11
2019
pubmed:
18
12
2019
medline:
24
3
2021
entrez:
18
12
2019
Statut:
ppublish
Résumé
Binding of transcription factors to mutated DNA sequences is a likely regulator of cancer progression. Noncoding regulatory mutations such as those on the core promoter of the gene encoding human telomerase reverse transcriptase have been shown to affect gene expression in cancer. Using a protein microarray of 667 transcription factor DNA-binding domains and subsequent functional assays, we looked for transcription factors that preferentially bind the mutant hTERT promoter and characterized their downstream effects. One of them, friend leukemia integration 1 (FLI1), which belongs to the E26 transforming-specific family of transcription factors, exhibited particularly strong effects with respect to regulating hTERT expression, while the even better binding ELK3 did not. Depletion of FLI1 decreased expression of the genes for cyclin D1 (CCND1) and E2F transcription factor 2 (E2F2) resulting in a G1/S cell cycle arrest and in consequence a reduction of cell proliferation. FLI1 also affected CMTM7, another gene involved in G1/S transition, although by another process that suggests a balanced regulation of the tumor suppressor gene's activity via opposing regulation processes. FLI1 expression was found upregulated and correlated with an increase in CCND1 expression in pancreatic cancer and brain tumors. In non-neoplastic lung cells, however, FLI1 depletion led to rapid progression through the cell cycle. This coincides with the fact that FLI1 is downregulated in lung tumors. Taken together, our data indicate a cell cycle regulatory hub involving FLI1, hTERT, CCND1 and E2F2 in a tissue- and context-dependent manner.
Substances chimiques
CCND1 protein, human
0
Cell Cycle Proteins
0
E2F2 Transcription Factor
0
E2F2 protein, human
0
FLI1 protein, human
0
Proto-Oncogene Protein c-fli-1
0
Cyclin D1
136601-57-5
TERT protein, human
EC 2.7.7.49
Telomerase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
189-201Informations de copyright
© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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