Specificity Protein Transcription Factors and Cancer: Opportunities for Drug Development

Abstract

Specificity protein (Sp) transcription factors (TFs) such as Sp1 are critical for early development but their expression decreases with age and there is evidence that transformation of normal cells to cancer cells is associated with upregulation of Sp1, Sp3, and Sp4, which are highly expressed in cancer cells and tumors. Sp1 is a negative prognostic factor for pancreatic, colon, glioma, gastric, breast, prostate, and lung cancer patients. Functional studies also demonstrate that Sp TFs regulate genes responsible for cancer cell growth, survival, migration/invasion, inflammation and drug resistance, and Sp1, Sp3 and Sp4 are also nononcogene addiction (NOA) genes and important drug targets. The mechanisms of drug-induced downregulation of Sp TFs and pro-oncogenic Sp-regulated genes are complex and include ROS-dependent epigenetic pathways that initially decrease expression of the oncogene cMyc. Many compounds such as curcumin, aspirin, and metformin that are active in cancer prevention also exhibit chemotherapeutic activity and these compounds downregulate Sp TFs in cancer cell lines and tumors. The effects of these compounds on downregulation of Sp TFs in normal cells and the contribution of this response to their chemopreventive activity have not yet been determined. .

RNA sequencing reveals a key role for the long non-coding RNA MIAT in regulating neuroblastoma and glioblastoma cell fate

“…Among the various family members, Sp1, Sp3 and Sp4 have gained attention, with Sp1 being the subject of thorough investigation [53], and importantly all three members displayed at least a three-fold decrease upon MIAT knockdown in our RNA sequencing, and in addition, numerous regulators of Sp1, including various miRNAs ( Supplementary table 2) and eighteen members of the ZBTB (zing finger and BTB) family were significantly deregulated. Since the elevated activity of Sp1 has been associated with malignancy and tumour progression in various cancers including glioma [53]- [55], it could be assumed that its downregulation could prevent this effect. In fact, a reasonable mechanism would suggest that MIAT knockdown induces an increase in ROS production, which in turn induces a ROS-mediated epigenetic downregulation of c-MYC [56] leading to the downregulation of Sp1 via the regulation of miRNAs and ZBTB proteins.…”

“…Sps belong to the Sp/Krüppel-like factor (KLF) family of TFs and play important roles in healthy and pathological settings, including cancer [52]. Among the various family members, Sp1, Sp3 and Sp4 have gained attention, with Sp1 being the subject of thorough investigation [53], and importantly all three members displayed at least a three-fold decrease upon MIAT knockdown in our RNA sequencing, and in addition, numerous regulators of Sp1, including various miRNAs ( Supplementary table 2) and eighteen members of the ZBTB (zing finger and BTB) family were significantly deregulated. Since the elevated activity of Sp1 has been associated with malignancy and tumour progression in various cancers including glioma [53]- [55], it could be assumed that its downregulation could prevent this effect.…”

NCBP1 promotes the development of lung adenocarcinoma through up‐regulation of CUL4B

“…Many cancer therapies, both chemotherapeutics and radiation therapies, act by inhibiting cell division and proliferation. Recently, attention has focused on post‐transcriptional regulation as a promising pathway in cancer therapeutics . Gene expression in advanced eukaryotic cells involves multiple processes including transcription, splicing, nuclear export and translation.…”

“…Recently, attention has focused on posttranscriptional regulation as a promising pathway in cancer therapeutics. 2,3 Gene expression in advanced eukaryotic cells involves multiple processes including transcription, splicing, nuclear export and translation. During these stages, specific nuclear proteins are recruited to regulate the production of nascent pre-mRNA, resulting in the export of mature mRNA to the cytoplasm.…”

Small Protein Hidden in lncRNA LOC90024 Promotes “Cancerous” RNA Splicing and Tumorigenesis

“…[ 3–5 ] Sp4 is a general TF that binds to and acts through GC base boxes, which are frequently occurring DNA elements present in many promoters and enhancers. [ 14 ] We found that SRSP promoted the inclusion of exon 3 of TF Sp4 to promote long Sp4 splicing variant formation (we termed L‐Sp4) and suppress short Sp4 splicing variant formation without exon 3 (we termed S‐Sp4) ( Figure A). The skipping of exon 3 of Sp4 was confirmed by targeted RNA‐seq when SRSP expression was knocked out (Figure 5B).…”