RNA-seq study of a helicon peptide targeting β-Catenin/TCF transcription factor [in vitro]

Genetic and epigenetic alterations in the Wnt signaling pathway leading to constitutive activation of the driver oncogene β-catenin occur in at least 20% of all human cancers. Pharmacologic suppression of aberrant β-catenin transcriptional activity through direct targeting of its downstream effectors has proven elusive despite decades of effort. We developed conformationally hyperstabilized α-helical peptides – which we refer to as Helicons – that directly bind β-catenin with sub-nanomolar affinity and exhibit good cytosolic exposure. COLO320DM is a human colorectal cancer line with an activated Wnt/ β-catenin pathway driven by an APC mutation. Here, we characterize the global effects of Helicon treatment on COLO320DM cells in vitro by whole-transcriptome RNA sequencing. As expected, Helicon 4 treatment had both time- and dose-dependent effects on the COLO320DM transcriptional profile. In particular, the Hallmark Wnt/β-catenin gene set was significantly down-regulated as early as six-hour at 10uM. The result validates the on-target inhibition of β-catenin signaling through disruption of its interaction with TCF/LEF transcription factors by active Helicons. COLO320DM is a human colorectal cancer line with an activated Wnt/ β-catenin pathway driven by an APC mutation. Here, we characterized the global effects of Helicon treatment on COLO320DM cells in vitro by whole-transcriptome RNA sequencing. As expected, Helicon 4 treatment had both time- and dose-dependent effects on the COLO320DM transcriptional profile. In particular, the Hallmark Wnt/β-catenin gene set was significantly down-regulated in as early as six -hours at 10 μuM. The result validates the on-target inhibition of β-catenin signaling through disruption of its interaction with TCF/LEF transcription factors by active Helicons.