Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with increases in new cases being reported annually. Histopathologists have identified hepatic steatosis as a characteristic of a broad range of chronic liver diseases that are associated with the onset and development of HCC. In this context, epigenetic modifications may serve as precancerous factors predisposing normal cells to the initiation of carcinogenesis. This study demonstrated that hepatic tumorigenesis and differentiated adipocytes may modulate both global histone deacetylase (HDAC) expression and specific class I HDAC genes in the tumour microenvironment. The novel class I HDAC inhibitor Resminostat was shown to reduce the proliferation of HCC cells along with its specificity in targeting class I HDACs and oncogenes. The combined effect of Resminostat with several pharmaceutical agents such as Sorafenib, Cisplatin and Doxorubicin was also demonstrated. The inhibition of heat shock protein 90 (HSP90) has been demonstrated as a potential therapeutic option for HCC. In line with this, the specific HSP90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) was selected and it was found that the combination of Resminostat and 17-AAG may provide a “smart” clinical strategy for HCC patients by targeting cellular communication within the tumour microenvironment. This study provides an insight into the use of Resminostat as an epigenetic based therapeutic for HCC along with other pharmaceutical options, in particular by targeting the cell-to-cell communication that occurs between hepatoma and adipocytes.
Highlights
The concept of epigenetics was first introduced as an important element in embryonic development by Conrad Hal Waddington in 1942 [1]
A recent cohort study carried out in 170 hepatocellular carcinoma (HCC) patients has shown that class I histone deacetylase (HDAC) (HDAC 1, 2 and 3) were highly expressed in HCC tumour tissues compared to adjacent normal tissues [8]
We found that differentiated human adipocytes had 62.33% less HDAC activity compared to HCC cells (Figure 1A)
Summary
The concept of epigenetics was first introduced as an important element in embryonic development by Conrad Hal Waddington in 1942 [1]. While the onset and development of hepatocellular carcinoma (HCC) have been attributed to several factors at both cellular and physiological levels, epigenetic alterations are receiving an increased attention in the investigation of the pathogenesis and pharmaceutical targeting of liver cancer due to their nature of reversibility. DNA strands are coiled around the histone tails to form chromatin Histone modifications such as acetylation/ deacetylation and methylation on histone tails allow the activation or inhibition of specific genes, the aberrant expression of which are associated with HCC onset and progression. The recent SHELTER study examining Resminostat in combination with Sorafenib showed a promising 8 month survival time for advanced HCC patients [13]
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