Critical role of hnRNP A1 in activating KRAS transcription in pancreatic cancer cells: A molecular mechanism involving G4 DNA

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 5; pp. 1389 - 1398
• Main Authors: Cogoi, Susanna, Rapozzi, Valentina, Cauci, Sabina, Xodo, Luigi E.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2017
• Subjects: adenocarcinoma; Binding Sites; carcinogenesis; DNA; DNA conformation; DNA, Neoplasm - chemistry; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; G-quadruplex; G-Quadruplexes; G4 unfolding; Gene Expression Regulation, Neoplastic; genes; Guanosine - chemistry; Guanosine - metabolism; Heterogeneous Nuclear Ribonucleoprotein A1; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - chemistry; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism; hnRNP A1; Humans; KRAS oncogene; Ligands; neoplasm cells; nuclear proteins; Pancreatic cancer; pancreatic neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; phenotype; Polymorphism, Genetic; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Structure-Activity Relationship; Transcription regulation; Transcription, Genetic; Transcriptional Activation; G4 unfolding; KRAS oncogene; Pancreatic cancer; G-quadruplex; hnRNP A1; Transcription regulation
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2016.11.031

KRAS is one of the most mutated genes in human cancer. Its crucial role in the tumourigenesis of pancreatic ductal adenocarcinoma (PDAC) has been widely demonstrated. As this deadly cancer does not sufficiently respond to conventional chemotherapies, it is important to increase our knowledge of pancreatic cancer biology, in particular how oncogenic KRAS is regulated. The promoter of KRAS contains a GA-element composed of runs of guanines that fold into a G4 structure. This unusual DNA conformation is recognized by several nuclear proteins, including MAZ and hnRNP A1. Recent data have revealed that KRAS is interconnected to ILK and hnRNP A1 in a circuitry that enables pancreatic cancer cells to maintain an aggressive phenotype. The present review illustrates recent advances on how KRAS is regulated in pancreatic cancer cells, focusing on the formation of G4 structures in the KRAS promoter and their interaction with hnRNP A1. The newly discovered KRAS-ILK-hnRNP A1 regulatory loop is discussed, emphasizing its potential as a therapeutic target for PDAC-specific molecules. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio. [Display omitted] •KRAS promoter contains upstream of TSS a critical GA-element forming a G-quadruplex behaving as a transcriptional repressor.•The KRAS G-quadruplex is recognised by several nuclear proteins that include PARP-1, Ku70, MAZ and hnRNP A1.•Upon binding to the KRAS G-quadruplex, hnRNP A1 unfolds the structure and favours transcription.•hnRNP A1 is a component of the KRAS-E2F1-ILK-hnRNP A1 loop that regulates oncogenic KRAS in pancreatic cancer.•The KRAS-E2F1-ILK-hnRNP A1 loop provides targets for molecules aiming to suppress proliferation of pancreatic cancer cells.