GLI1, a master regulator of the hallmark of pancreatic cancer

Abstract

Hedgehog signaling is highly conserved across species and governs proper embryonic development. Germline gene mutations that reduce this signaling activity cause a variety of developmental abnormalities such as holoprosencephaly, while those that enhance Hedgehog signaling activity induce a tumor-predisposition condition Nevoid basal cell carcinoma syndrome. Furthermore, dysregulated activation of Hedgehog signaling has been recognized in various sporadic malignancies, including pancreatic adenocarcinoma. Pancreatic adenocarcinoma develops through a multistep carcinogenesis starting with oncogenic mutation of the KRAS gene. During this process, precancerous or cancer cells secrete Hedgehog ligand proteins to promote characteristic desmoplastic stroma around the cells, which in turn activates the expression of the downstream transcription factor GLI1 inside the cells. The quantitative and spatiotemporal dysregulation of GLI1 subsequently leads to the expression of transcriptional target genes of GLI1 that govern the hallmark of malignant properties. Here, after a brief introductory outline, a perspective is offered of Hedgehog signaling with a special focus on the role of GLI1 in pancreatic carcinogenesis.

Targeting Transcription Factors for Cancer Treatment

“…Many transcription factors are associated with multiple of these hallmarks of cancers and are therefore defined as oncogenes (see Table 1 ). Among them are NFκB, P53, MYC, HIF-1, STATs, GLI1, ERG, RUNX1, FOXO, HOXs and NRF2 [ 418 , 419 , 420 , 421 , 422 , 423 , 424 , 425 , 426 , 427 ], all transcription factors against which inhibitors are developed as presented along this manuscript. For a long time, transcription factors (other than nuclear receptors for which derivatives of natural ligands have be developped) were considered as undruggable targets and indirect strategies were developed in parallel to their association to cancer processes such as the epigenetic control of their expression.…”

Pituitary stem cell regulation: who is pulling the strings?

“…Aberration of SHH signaling has been linked with tumorigenesis in various tissues, as for instance found in pancreas (Kasai 2016), bladder (Syed et al 2016) and prostate (Peng & Joyner 2015). Similar to the NOTCH pathway, SHH activity appears to differ according to pituitary adenoma subtype.…”

Inhibition of Hedgehog Signaling in Fibroblasts, Pancreatic, and Lung Tumor Cells by Oxy186, an Oxysterol Analogue with Drug-Like Properties

“…Many Hh-dependent cancers are driven by activating mutations that occur downstream of Smo, affecting the transcription factors known as glioma-associated oncogenes ( Gli1–3 ), which mediate the transcriptional effects of Hh pathway activation [18]. Numerous studies point to the significance of Gli activity in tumor cells, as well as the tumor microenvironment, particularly with stroma rich tumors, such as PDAC [19,20,21]. Inappropriate Hh signaling has been reported to occur at least in part via a paracrine signaling mechanism in which the expression and secretion of Hh ligand by tumor cells entails the subsequent activation of the canonical Hh signaling in adjacent stromal cells [22,23], although the role of paracrine Hh signaling in the pathogenesis of cancer has become a controversial topic [24,25].…”