Colorectal cancer is the third leading cause of cancer deaths in the United States, underscoring the critical need for new discoveries in tumor biology, new targets for the development of anti-cancer agents, and new innovative treatment approaches. We have demonstrated that aberrant signaling via the Hedgehog (HH) pathway is critical to the survival of colon cancer cells, contributing significantly to genomic instability, oncogenesis, progression and metastasis. Canonical HH signaling engages the transmembrane receptor PTCH, the signaling molecule SMO, and the transcriptional regulators of HH target genes, GLI1 and GLI2. We have demonstrated in colon cancer that oncogene-driven signaling pathways, specifically KRAS/BRAF, aberrantly converge on and activate GLI genes, integrating at the level of GLI2, and circumvent the HH-SMO axis. GANT61, a small molecule inhibitor of GLI1/GLI2 transcription, induces extensive cell death in human colon carcinoma cell lines in contrast to targeting SMO, thereby terminating KRAS/BRAF signaling, and delineating GLI as a critical target. During prolonged GANT61 exposure, GLI1, GLI2 and target gene promoters are coordinately regulated by H3K9 methylation to promote gene silencing and reduction in cell cycle transition at G1/S, delineating a unique mechanism to avoid cell death from GLI targeting. How GLI and GLI2 are regulated in normal cells or in cancer cells remains poorly understood, yet GLI marks an important target in tumor biology and for drug development. These approaches will provide new insight into critical targets that determine HH-dependent survival, and to translation of agents that target GLI.
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Shi T, Mazumdar T, DeVecchio J, Duan Z-H, Agyeman A, Aziz M, Houghton JA. cDNA microarray gene expression profiling of Hedgehog signaling pathway inhibition in human colon cancer cells. PLoS ONE 5: pii: e13054, 2010.
Mazumdar T, DeVecchio J, Agyeman A, Shi T, Houghton JA. Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells. Cancer Res 71:5904-5914, 2011.
Mazumdar T, DeVecchio J, Agyeman A, Shi T, Houghton JA. The GLI genes as the molecular switch in disrupting Hedgehog signaling in colon cancer. Oncotarget 2:638-645, 2011.
AgyemanA, Mazumdar T, Houghton JA. Regulation of DNA damage following termination of Hedgehog (HH) survival signaling at the level of the GLI genes in human colon cancer. Oncotarget 8:854-868, 2012.