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2016 ; 7
(49
): 80190-80207
Nephropedia Template TP
gab.com Text
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Twit Text #
English Wikipedia
Targeting GLI by GANT61 involves mechanisms dependent on inhibition of both
transcription and DNA licensing
#MMPMID27863397
Zhang R
; Wu J
; Ferrandon S
; Glowacki KJ
; Houghton JA
Oncotarget
2016[Dec]; 7
(49
): 80190-80207
PMID27863397
show ga
The GLI genes are transcription factors and in cancers are oncogenes, aberrantly
and constitutively activated. GANT61, a specific GLI inhibitor, has induced
extensive cytotoxicity in human models of colon cancer. The FOXM1 promoter was
determined to be a transcriptional target of GLI1. In HT29 cells, inhibition of
GLI1 binding at the GLI consensus sequence by GANT61 led to inhibited binding of
Pol II, the pause-release factors DSIF, NELF and p-TEFb. The formation of R-loops
(RNA:DNA hybrids, ssDNA), were reduced by GANT61 at the FOXM1 promoter.
Pretreatment of HT29 cells with ?-amanitin reduced GANT61-induced ?H2AX foci.
Co-localization of GLI1 and BrdU foci, inhibited by GANT61, indicated GLI1 and
DNA replication to be linked. By co-immunoprecipitation and confocal microscopy,
GLI1 co-localized with the DNA licensing factors ORC4, CDT1, and MCM2.
Significant co-localization of GLI1 and ORC4 was inhibited by GANT61, and
enrichment of ORC4 occurred at the GLI binding site in the FOXM1 promoter. CDT1
was found to be a transcription target of GLI1. Overexpression of CDT1 in HT29
and SW480 cells reduced GANT61-induced cell death, gH2AX foci, and cleavage of
caspase-3. Data demonstrate involvement of transcription and of DNA replication
licensing factors by non-transcriptional and transcriptional mechanisms in the
GLI-dependent mechanism of action of GANT61.