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A unique acquired resistance mechanism to agents that target GLI (GANT61) in the Hedgehog (HH) signaling pathway
Author(s) -
Agyeman Akwasi,
Mazunder Tapati,
Houghton Janet
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.772.3
Subject(s) - gli1 , gli2 , biology , cancer research , foxm1 , hedgehog , carcinogenesis , hedgehog signaling pathway , signal transduction , promoter , transcription factor , microbiology and biotechnology , gene , genetics , gene expression
Canonical HH signaling engages the transmembrane receptor PTCH, the intermediary signaling molecule SMO, and the HH signaling response molecules, GLI1 and GLI2. In colon cancers, GLI is aberrantly regulated, driving cell survival and genomic instability in oncogenesis, progression and metastasis. Following inhibition of GLI by a protracted exposure of HT29 to GANT61, we have identified a previously undescribed, novel mechanism by which cancer cells evade cell death. Stepwise selection did not produce a proliferative colon cancer cell line resistant to GANT61, confirming the critical importance of GLI genes to cell survival. In contrast, in HT29 cells, by inhibiting GLI1/GLI2 by prolonged exposure to semi‐lethal concentrations of GANT61 (10 μM; G10), we observed reduced proliferation, decreased appearance of γH2AX nuclear foci, and increased methylation of histone H3K9 (H3K9me1–3) within the promoters of the GLI1 and GLI2 genes. Increased H3K9 methylation was also demonstrated in HT29(G10) cells in the promoter regions of FoxM1 and CDC6, a G1/S and PreReplication Complex assembly regulatory genes, respectively. Data suggest that the GLI2‐>;GLI1‐>;FOXM1‐>;CDC6 promoters are coordinately regulated by H3K9 methylation in a pathway to promote gene silencing, reduce gene transcription, and reduce cell cycle transition at G1/S, constituting a unique mechanism of acquired resistance to drugs that target GLI. This work is supported by NCI awards RO1 CA 32613 (J.A. Houghton) and NCI RO1 108929 (J.A. Houghton)