Abstract
Hedgehog signaling plays very important roles in development and cancers. Vertebrates have three transcriptional factors, Gli1, Gli2 and Gli3. Among them, Gli3 is a very special transcriptional factor which closely resembles Cubitus interruptus (Ci, in Drosophila) structurally and functionally as a 'double agent' for Shh target gene expression. Here we show that Gli3 full-length, but not the truncated form, can be methylated at K436 and K595. This methylation is specifically catalyzed by Set7, a lysine methyltransferase (KMT). Methylation at K436 and K595 respectively increases the stability and DNA binding ability of Gli3, resulting in an enhancement of Shh signaling activation. Furthermore, functional experiments indicate that the Gli3 methylation contributes to the tumor growth and metastasis in non-small cell lung cancer in vitro and in vivo. Therefore, we propose that Set7 mediated methylation is a novel PTM of Gli3, which positively regulates the transactivity of Gli3 and the activation of Shh signaling.
Highlights
Hedgehog (Hh) signaling plays critical roles in embryonic development and tumor growth (Chen et al, 2007; Hooper and Scott, 2005; Ingham and McMahon, 2001; Nieuwenhuis and Hui, 2005; Yao and Chuang, 2015)
To further test if the methylations on K436 and K595 are catalyzed by Set7, in vitro methylation assays were performed by incubating MBP-tagged peptides of Gli3, MBP-K436 or MBP-K595 with GST-Set7 and 3H-SAM (Figure 1A, lower panel)
We demonstrated that Set7 can exclusively methylate Gli3 full-length at K436 and K595 sites in vitro and in vivo
Summary
Hedgehog (Hh) signaling plays critical roles in embryonic development and tumor growth (Chen et al, 2007; Hooper and Scott, 2005; Ingham and McMahon, 2001; Nieuwenhuis and Hui, 2005; Yao and Chuang, 2015). Hh pathway is activated when Hh ligands (Shh, Ihh or Dhh) bind to their repressive receptor Patched (Ptc), a twelve-transmembrane protein, leading to alleviation of its repression on the signaling transducer, Smoothened (Smo), a seven-transmembrane protein. The unleashed Smo can activate the Gli transcription factors, resulting in the expression of downstream target genes, like Gli and Ptch. Gli draws considerable attentions due to its structural and functional similarity to Ci. Like Ci, Gli plays critical roles in modulating the switch-on and -off of Shh signaling. In the absence of Shh signaling, Gli is partially proteolyzed into a truncated transcriptional repressor (Gli3R) to block the expression of downstream target genes. In the presence of Shh signaling, Gli is in a full-length transactivation form and activates the expression of downstream genes like Gli and Ptch (Dai et al, 1999; 2002)
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