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Carcinogenesis ; 42(8): 1026-1036, 2021 08 19.
Article in English | MEDLINE | ID: mdl-33999989

ABSTRACT

Hepatocellular carcinoma (HCC) presents with a high treatment resistance and poor prognosis. Early diagnosis and preventive approaches such as chemoprevention are essential for the HCC control. Therefore, we evaluated the chemopreventive effects of butyrate-containing structured lipids (STLs) administered during the promotion stage of hepatocarcinogenesis in rats submitted to the 'resistant hepatocyte' (RH) model. Administration of butyrate-containing STLs inhibited the incidence and mean number of visible hepatic nodules per rat and reduced the number and area of glutathione S-transferase placental form-positive (GST-P+) preneoplastic focal lesions in the livers. This was accompanied by the induction of apoptosis and an increased level of hepatic butyric acid. Treatment with butyrate-containing STLs resulted in increased histone H3 lysine 9 (H3K9) acetylation, reduction of total histone deacetylase (HDAC) activity, and lower levels of HDAC4 and HDAC6 proteins. The chemopreventive effect of butyrate-containing STLs was also associated with the increased nuclear compartmentalization of p53 protein and reduced expression of the Bcl-2 protein. In addition, rats treated with butyrate-containing STLs showed decreased DNA damage and telomerase activity in the livers. These results demonstrate that the suppressive activity of butyrate-containing STLs is associated with inhibition of elevated during hepatocarcinogenesis chromatin-modifying proteins HDAC4 and HDAC6, subcellular redistribution of the p53 protein, and decreased DNA damage and telomerase activity.


Subject(s)
Butyrates/metabolism , DNA Damage , Glutathione S-Transferase pi/metabolism , Histone Deacetylase 6/metabolism , Histone Deacetylases/metabolism , Lipids/chemistry , Liver Neoplasms, Experimental/pathology , Telomerase/metabolism , Animals , Carcinogenesis , Caspase 3/metabolism , Liver Neoplasms, Experimental/enzymology , Liver Neoplasms, Experimental/genetics , Male , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Wistar , Subcellular Fractions/enzymology , Tumor Suppressor Protein p53/metabolism , alpha-Linolenic Acid/metabolism
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