Abnormal expression of TFIIIB subunits and RNA Pol III genes is associated with hepatocellular carcinoma

Abstract

The levels of the products of RNA polymerase III-dependent genes (Pol III genes), including tRNAs and 5S rRNA, are elevated in transformed and tumor cells, which potentiate tumorigenesis. TFIIB-related factor 1 (Brf1) is a key transcription factor and specifically regulates the transcription of Pol III genes. In vivo and in vitro studies have demonstrated that a decrease in Brf1 reduces Pol III gene transcription and is sufficient for inhibiting cell transformation and tumor formation. Emerging evidence indicates that dysregulation of Brf1 and Pol III genes is linked to the development of hepatocellular carcinoma (HCC) in humans and animals. We have reported that Brf1 is overexpressed in human liver cancer patients and that those with high Brf1 levels have shorter survivals. This review summarizes the effects of dysregulation of these genes on HCC and their regulation by signaling pathways and epigenetics. These novel data should help us determine the molecular mechanisms of HCC from a different perspective and guide the development of therapeutic approaches for HCC patients.

Keywords: Hepatocellular carcinoma (HCC); Histone H3; RNA polymerase III; TFIIB-related factor 1 (Brf1); c-Jun amino-terminal kinase (JNKs).

Fig. 1. TFIIIB subunits are recruited to the promoter of Pol III genes

(A) Transcriptional machinery of tRNA genes includes Pol III, TFIIIC, and TFIIIB in the regulatory region of tRNAs. TFIIIB subunits (Brf1, TBP, Bdp1) interact with oncogenic proteins and suppressors. (B) Transcriptional machinery of 5S rRNA has Pol III, TFIIIA, TFIIIC, and TFIIIB in the regulatory region of 5S rRNA. A, B, and ICR are the regulatory elements in the promoter regions of tRNA and 5S rRNA genes. tRNAs and 5S rRNA, the concentrations of which increase in transformed cells and tumor tissues, have important roles in protein synthesis. Abbreviations: Pol III, RNA polymerase III; TBP, TATA box-binding protein; Brf1, TFIIB-related factor 1.

Fig. 2. Signaling events of stimulator-induced liver tumor development

Stimulators induce JNK1 activation to upregulate c-Jun expression through Elk-1. Elk-1 and c-Jun augment TBP and Brf1 expression to upregulate Pol III gene transcription, resulting in cell proliferation and cell transformation and eventual HCC development. Blue P: phosphorylation group. Abbreviations: Pol III, RNA polymerase III; TBP, TATA box-binding protein; Brf1, TFIIB-related factor 1; JNKs, c-Jun amino-terminal kinase; HCC, hepatocellular carcinoma.

Fig. 3. Chromatin remodeling by MSK1-mediated H3ph

These factors activate MAP kinases, which in turn stimulate MSK1 (MSK1ph). MSK1ph mediates H3ph to effect chromatin remodeling, leading to transcription of Pol III genes. Blue P: phosphorylation group. Abbreviations: MAPKs, mitogen-activated protein kinases; H3ph, histone H3 phosphorylation; Pol III, RNA polymerase III.