Gli Proteins Up-Regulate the Expression of Basonuclin in Basal Cell Carcinoma

Abstract

Tumorigenesis is frequently accompanied by enhanced rRNA transcription, but the signaling mechanisms responsible for such enhancement remain unclear. Here, we report evidence suggesting a novel link between deregulated Hedgehog signaling and the augmented rRNA transcription in cancer. Aberrant activation of the Hedgehog pathway in keratinocytes is a hallmark of basal cell carcinoma (BCC), the most common cancer in light-skinned individuals. We show that Gli proteins, downstream effectors of the Hedgehog pathway, increase expression of a novel rRNA gene (rDNA) transcription factor, basonuclin, whose expression is markedly elevated in BCCs. The promoter of the human basonuclin gene contains a Gli-binding site, which is required for Gli protein binding and transcriptional activation. We show also that the level of 47S pre-rRNA is much higher in BCCs than in normal epidermis, suggesting an accelerated rRNA transcription in the neoplastic cells. Within BCC, those cells expressing the highest level of basonuclin also exhibit the greatest increase in 47S pre-rRNA, consistent with a role for basonuclin in increasing rRNA transcription in these cells. Our data suggest that Hedgehog-Gli pathway enhances rRNA transcription in BCC by increasing basonuclin gene expression.

Basal cell carcinoma: biology, morphology and clinical implications

“…67 Upregulation of Gli proteins (Figures 18 and 19) has been shown by quantitative reverse transcriptase polymerase chain reaction assay in BCC 68,69 and may play an important role in the initiation of BCC through the activation of the BCL2 gene ( Figure 20). 70 Gli proteins are also downstream regulators of the SHH signaling pathway, leading to increased tRNA expression through the basonuclin gene system 71 and possibly as well through the forkhead/wingedhelix domain transcription factor FOXE-1. 72 Increased FOXM-1 levels, upregulated through shh signalling via Gli1, may be specific for sporadic BCC.…”

Basonuclin: a novel mammalian maternal-effect gene

“…Consistent with this proposal is that although we detect reduced rates of Pol I transcription using the run-on assay, the level of mature rRNA and protein synthesis remain unchanged in fully grown basonuclin-deficient oocytes. Another sign that a compensatory mechanism exists is that microarray analysis of basonuclin-deficient oocytes reveals a large number of upregulated genes, and the most notable among them is a ~16-fold increase in abundance of Gli2 mRNA, which encodes a transcriptional effector (GLI2) that can upregulate basonuclin transcription (Cui et al, 2004). Upregulation of Gli2 in basonuclin-deficient oocytes suggests an apparently futile attempt of the transgenic oocytes to compensating for the reduced level of basonuclin mRNA by increasing its transcription.…”

Chronologic aging decreases tumor angiogenesis and metastasis in a mouse model of head and neck cancer

“…The Jumonji domain containing transcriptional repressors Jarid1a and Jarid2 have potential tumor suppressor function (28), and their expression is inhibited in tumors from chronologically aged mice. The basonuclin transcription factor is markedly upregulated in basal cell carcinoma in epidermis (29), and also in metastatic tumor cells from chronologically aged mice. Elements of the Wnt signaling pathway were altered in HNSCC such as upregulation of Wnt4, Wnt10a, and frizzled homolog 2 in metastatic tumors from chronologically aged mice.…”