Liver-Targeting Class I Selective Histone Deacetylase Inhibitors Potently Suppress Hepatocellular Tumor Growth as Standalone Agents

Abstract

Dysfunctions in epigenetic regulation play critical roles in tumor development and progression. Histone deacetylases (HDACs) and histone acetyl transferase (HAT) are functionally opposing epigenetic regulators, which control the expression status of tumor suppressor genes. Upregulation of HDAC activities, which results in silencing of tumor suppressor genes and uncontrolled proliferation, predominates in malignant tumors. Inhibition of the deacetylase activity of HDACs is a clinically validated cancer therapy strategy. However, current HDAC inhibitors (HDACi) have elicited limited therapeutic benefit against solid tumors. Here, we disclosed a class of HDACi that are selective for sub-class I HDACs and preferentially accumulate within the normal liver tissue and orthotopically implanted liver tumors. We observed that these compounds possess exquisite on-target effects evidenced by their induction of dose-dependent histone H4 hyperacetylation without perturbation of tubulin acetylation status and G0/G1 cell cycle arrest. Representative compounds 2 and 3a are relatively non-toxic to mice and robustly suppressed tumor growths in an orthotopic model of HCC as standalone agents. Collectively, our results suggest that these compounds may have therapeutic advantage against HCC relative to the current systemic HDACi. This prospect merits further comprehensive preclinical investigations.

Inflammation, Fibrosis and Cancer: Mechanisms, Therapeutic Options and Challenges

“…Earlier studies have explored the potential of the intratumoral administration of a short-chain fatty acid HDACi (4-phenylbutyrate) and a HDACi pro-drug (hyaluronate-butyrate) designed to target membrane receptor CD44 on liver sinusoidal epithelial cells [279,280]. A more recent study disclosed and characterized macrolide-based liver-tissue accumulating selective HDAC 1 inhibitors [281]. These studies revealed that these delivery strategies facilitated potent HDAC inhibition at the disease site, which resulted in a significant repression of HCC tumor growth and metastatic spread.…”

Roles and regulation of histone acetylation in hepatocellular carcinoma

“…Recently, quantitative acetylome analysis and lysine acetylome study revealed that abnormal histone modifications may predict prognosis in HCC patients ( Zhao et al, 2020 ; Chai et al, 2021 ). Furthermore, several liver-targeting HDAC inhibitors potently suppress HCC growth and animal and preclinical studies with HDAC inhibitors suggest survival benefits ( Yeo et al, 2012 ; Afaloniati et al, 2020 ; Tapadar et al, 2020 ). However, the role of acetylated proteins and the precise mechanism of individual HDACs in HCC progression is still not clear.…”

Deciphering a mitochondria-related signature to supervise prognosis and immunotherapy in hepatocellular carcinoma

“…Hepatocellular carcinoma (HCC) is the second cause of cancer-related death, characterized by an advanced stage at the first diagnosis, threatening public health security and human happiness ( 1 ). Genetic and epigenetic alterations give rise to extensive tumor heterogeneity, which results in an unsatisfactory prognosis and a heavy disease burden for HCC patients ( 2 , 3 ). Moreover, the 5-year survival rate of HCC patients is about 40% after radical hepatectomy ( 4 ).…”