Transcriptional regulators in hepatocarcinogenesis – Key integrators of malignant transformation

Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies with poor prognosis and increasing incidence in the Western world. Only for a minority of HCC patients, surgical treatment options offer potential cure and therapeutic success of pharmacological approaches is limited. Highly specific approaches (e.g., kinase inhibitors) did not significantly improve the situation so far, possibly due to functional compensation, genetic heterogeneity of HCC, and development of resistance under selective pressure. In contrast, transcriptional regulators (especially transcription factors and co-factors) may integrate and process input signals of different (oncogenic) pathways and therefore represent cellular bottlenecks that regulate tumor cell biology. In this review, we want to summarize the current knowledge about central transcriptional regulators in human hepatocarcinogenesis and their potential as therapeutic target structures. Genomic and transcriptomic data of primary human HCC revealed that many of these factors showed up in subgroups of HCCs with a more aggressive phenotype, suggesting that aberrant activity of transcriptional regulators collect input information to promote tumor initiation and progression. Therefore, expression and dysfunction of transcription factors and co-factors may gain relevance for diagnostics and therapy of HCC.

PI3K/AKT/mTOR‐dependent stabilization of oncogenic far‐upstream element binding proteins in hepatocellular carcinoma cells

“…The bow tie structure of signaling pathways facilitates control and robustness with regard to perturbations and fluctuations under physiological conditions . In this context, transcription factors (e.g., FBPs, c‐MYC, p53) or transcriptional coactivators (e.g., YAP, β‐catenin) represent structural pathway nodes that, if dysregulated, may cause or contribute to the development of liver cancer . FBPs are highly expressed in different human malignancies, and especially for HCC it has been demonstrated that their overexpression induces tumor cell proliferation and is correlated with poor overall survival .…”

Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma

“…Tumor‐relevant transcriptional regulators consist of DNA‐interacting transcription factors (e.g., c‐Myc, NF‐κB) and transcriptional coactivators (e.g., β‐catenin or YAP), which fine‐tune initiation, progression, and termination of the transcriptional machinery to regulate the expression of target genes in a time‐dependent manner. Because transcriptional regulators usually integrate and transfer a variety of input information from, e.g., growth factor signaling they are regarded as cellular bottlenecks, which represent promising therapeutic target structures in the treatment of cancer …”

“…Because transcriptional regulators usually integrate and transfer a variety of input information from, e.g., growth factor signaling they are regarded as cellular bottlenecks, which represent promising therapeutic target structures in the treatment of cancer. 1 Using a proteomic approach, the transcription factor far upstream element (FUSE) binding protein (FBP; syn. FUBP1), which is one of three family members, was identified as highly expressed in human HCC samples, 2 where it positively regulates HCC cell proliferation.…”

85 THE TRANSCRIPTION FACTOR c-JUN/AP-1 PROMOTES HBV-RELATED LIVER TUMORIGENESIS IN MICE

“…Expression of the AP-1 transcription factor c-Jun has been observed in many molecular subtypes of human HCC 20 and is particularly increased in HBV-related HCC. 21 c-Jun strongly promotes liver tumorigenesis in mouse models of chemically induced HCC [14][15][16] and also determines hepatocyte fate in a variety of inflammatory stress conditions including T-cellmediated hepatitis and ER stress, 8,12 suggesting that c-Jun may also contribute to the pathogenesis of hepatitisassociated HCC.…”