Abstract
The hepatocyte nuclear factor-4α (HNF4α) and hepatocyte nuclear factor-1α (HNF1α) are transcription factors that influence the development and maintenance of homeostasis in a variety of tissues, including the liver. As such, disruptions in their transcriptional networks can herald a number of pathologies, such as tumorigenesis. Largely considered tumor suppressants in liver cancer, these transcription factors regulate key events of inflammation, epithelial-mesenchymal transition, metabolic reprogramming, and the differentiation status of the cell. High-throughput analysis of cancer cell genomes has identified a number of hotspot mutations in HNF1α and HNF4α in liver cancer. Such results also showcase HNF1α and HNF4α as important therapeutic targets helping us step into the era of personalized medicine. In this review, we update current findings on the roles of HNF1α and HNF4α in liver cancer development and progression. It covers the molecular mechanisms of HNF1α and HNF4α dysregulation and also highlights the potential of HNF4α as a therapeutic target in liver cancer.
Highlights
Transcriptional factors (TFs) play a pivotal role in normal cellular physiology, and their aberrant expression is linked to a myriad of diseases [1]
The HNF family of TFs is implicated in mature onset diabetes of the young (MODY), and mutations in the hepatocyte nuclear factor-4α (HNF4α), hepatocyte Nuclear Factor 1α (HNF1α), and HNF1β genes cause MODY, a form of non-insulin-dependent diabetes mellitus [4,5,6]
HNF4α plays a role throughout the initiation, malignant transformation, and metastasis in liver cancer development by regulating the key events of inflammation [24,25], epithelial–mesenchymal transition (EMT) [26,27], and the differentiation status of the cells [11,28]
Summary
Transcriptional factors (TFs) play a pivotal role in normal cellular physiology, and their aberrant expression is linked to a myriad of diseases [1]. HNF4α plays a role throughout the initiation, malignant transformation, and metastasis in liver cancer development by regulating the key events of inflammation [24,25], epithelial–mesenchymal transition (EMT) [26,27], and the differentiation status of the cells [11,28]. Another liver-enriched TF, HNF1α acts synergistically with HNF4α to regulate gene expression in a variety of tissues and organs, including the liver, pancreas, and kidney [16,29]. Though HNFs are well-established tumor suppressants in the liver, their functional importance is yet to be elucidated
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