Molecular Mechanisms to Target Cellular Senescence in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death and is the most common type of liver cancer. Due to the current paucity of drugs for HCC therapy there is a pressing need to develop new therapeutic concepts. In recent years, the role of Serum Response Factor (SRF) and its coactivators, Myocardin-Related Transcription Factors A and B (MRTF-A and -B), in HCC formation and progression has received considerable attention. Targeting MRTFs results in HCC growth arrest provoked by oncogene-induced senescence. The induction of senescence acts as a tumor-suppressive mechanism and therefore gains consideration for pharmacological interventions in cancer therapy. In this article, we describe the key features and the functional role of senescence in light of the development of novel drug targets for HCC therapy with a focus on MRTFs.

Keywords: DLC1; HCC; MRTF; SRF; senescence; senolytics.

Figure 1

MRTFs and MYOF modulate proliferation and senescence upon DLC1 loss. Loss of the RhoGAP DLC1 results in Rho activation, which leads to actin polymerization, MRTF nuclear localization and expression of MRTF/SRF dependent target genes such as MYOF, resulting in enhanced HCC cell proliferation and migration. Depletion of MRTFs or MYOF inhibits HCC cell proliferation by inducing oncogene-induced senescence.

Figure 2

Pro-senescence cancer therapies to combat tumor growth. The accumulation of senescent cells in different tissues due to a reduced clearance as a result of, e.g. a compromised immune system leads to an increase in SASP factor secretion. This favors the development of age-related diseases and may counteract antitumor effects. The combination with senolytics may prevent an accumulation of senescent cells and the resulting deleterious effects of the SASP.

Figure 3

Summary of senescence events. Senescence is activated by a variety of different triggers, such as telomere shortening or oncogene overexpression. On the one hand, an accumulation of senescent cells and the subsequent secretion of SASP can be deleterious by resulting in aging, fibrosis and cancer. On the other hand, the induction of senescence combined with the clearance of senescent cells can be beneficial due to its tumor growth inhibition and suppression.