Abstract
Hepatocyte nuclear factor 4α (HNF4α) is a transcription factor that acts as a master regulator of genes for several endoderm-derived tissues, including the intestine, in which it plays a central role during development and tumorigenesis. To better define the mechanisms by which HNF4α can influence these processes, we identified proteins interacting with HNF4α using stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomics with either immunoprecipitation of green fluorescent protein (GFP) or with proximity-dependent purification by the biotin ligase BirA (BioID), both fused to HNF4α. Surprisingly, these analyses identified a significant enrichment of proteins characterized with a role in DNA repair, a so far unidentified biological feature of this transcription factor. Several of these proteins including PARP1, RAD50, and DNA-PKcs were confirmed to interact with HNF4α in colorectal cancer cell lines. Following DNA damage, HNF4α was able to increase cell viability in colorectal cancer cells. Overall, these observations identify a potential role for this transcription factor during the DNA damage response.
Highlights
The transcription factor hepatocyte nuclear factor 4α (HNF4α) regulates the development and differentiation of epithelia in digestive and accessory digestive organs [1,2,3]
Recent biological data have supported differential roles for these two classes of proteins in the colon with P1-Hepatocyte nuclear factor 4α (HNF4α) being functionally involved in suppressing the colon tumorigenesis [14,15,16]
We focused on identifying protein partners of P2-HNF4α based on its potential functional role as an oncogene during the colon tumorigenesis growth
Summary
The transcription factor hepatocyte nuclear factor 4α (HNF4α) regulates the development and differentiation of epithelia in digestive and accessory digestive organs [1,2,3]. HNF4α is expressed in the epithelia of the liver, pancreas, stomach, small intestine, and colon [4]. HNF4α controls the expression of genes involved in epithelial differentiation that are necessary for liver and pancreatic tissue [6] and important for the intestinal tissue [1,7,8]. Some later research suggested HNF4α to act as an oncoprotein in the intestine [11,12]. This apparent paradox could be explained by the existence of two isoform classes produced by two different promoters, namely P1 promoter-driven and P2 promoter-driven HNF4α isoforms [13]. It has recently been suggested that P1-HNF4α exerts a differentiative effect on intestinal epithelial cells while P2-HNF4α exerts a proliferative effect on these cells [14,15]
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