Abstract
As a physically binding protein of GLI1 transcription factor, Suppressor-of-Fused (SUFU) has been placed in the center of negative regulation of Hedgehog (Hh) signaling. SUFU tethers GLI1 in cytoplasm, and in some circumstances, it moves into the nucleus in association with GLI1, leading to the suppression of GLI1 target gene expression by recruiting a corepressor complex. The activated transcriptional function of GLI1 is important for cellular proliferation in a variety of human cancers. However, it has not been revealed how GLI1 is derepressed from SUFU-mediated suppression. Here, we show SCL/TAL1 interrupting locus (SIL) product, a cytoplasmic protein overexpressed in pancreatic ductal adenocarcinoma (PDA), is responsible for the derepression of GLI1. We found SIL associated with the carboxyl terminus of SUFU, one of two distinct GLI1-binding domains, and this association was responsible for cytoplasmic tethering of SUFU. Overexpressed SIL attenuated SUFU-mediated cytoplasmic tethering and target gene suppression of GLI1. Knockdown of SIL in PDA cells conversely induced the nuclear accumulation of SUFU in association with GLI1 and the transcriptional suppression of GLI1 target genes. Importantly, we also showed that oncogenic K-RAS, and not Sonic hedgehog, enhanced the SIL association with the amino-terminus of SUFU, the other GLI1-binding domain that led to further increase of nuclear translocation of GLI1. These results uncover the role of SIL in derepressing GLI1 from the negative control of SUFU, which is a crucial step for activating Hh signaling in cancer cells.
Highlights
The activity of GLI1 has been shown to be under the control of Suppressor-of-Fused (SUFU) by two distinct mechanisms
Using pancreatic ductal adenocarcinoma (PDA) cells, we have elucidated the molecular mechanisms of SCL/TAL1 interrupting locus (SIL) to regulate Hh signaling: SIL associates with SUFU and attenuates its suppressive role for GLI1, which is enhanced by oncogenic K-RAS but not Hh signaling itself
SIL expression was weakly detected in the basal side of normal duct epithelium, but its staining intensity significantly increased in the cytoplasm of pancreatic intraepithelial neoplasia (PanIN) and PDA cells
Summary
The activity of GLI1 has been shown to be under the control of Suppressor-of-Fused (SUFU) by two distinct mechanisms. Using PDA cells, we have elucidated the molecular mechanisms of SIL to regulate Hh signaling: SIL associates with SUFU and attenuates its suppressive role for GLI1, which is enhanced by oncogenic K-RAS but not Hh signaling itself. We first examined whether SIL might modify SUFU-mediated transcriptional suppression of GLI1 by luciferase reporter assay in KP1N and HEK293T cells (Fig. 1B), because we previously found that overexpressed SIL
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