Cancer is a disease in which cellular growth regulatory networks are disrupted. Lesions in well-characterized oncogenes and tumor suppressors often contribute to the dysregulation, but recent work has also uncovered the fundamental importance of enzymes that modulate the acetylation status of chromatin to the initiation or progression of cancer. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are known to be involved in physiological cellular processes, such as transcription, cell cycle progression, gene silencing, differentiation, DNA replication, and genotoxic responses, but they are also increasingly being implicated in tumorigenesis. Butyrate is a short-chain fatty acid (SCFA) that acts as a HDAC inhibitor and is being clinically evaluated as an anti-neoplastic therapeutic, primarily because of its ability to impose cell cycle arrest, differentiation, and/or apoptosis in many tumor cell types, and its favorable safety profile in humans. Additionally, HDAC inhibitors could be used in combination with certain established antitumor therapeutics, such as those that target transcription, to augment clinical efficacy, and/or reduce toxicity. The molecular pathways of butyrate and related next-generation synthetic SCFAs in mediating these effects have not been fully elucidated, but HDAC inhibition is associated with regulation of critical cell cycle regulators, such as cyclin D, p21(CIP1/WAF1), and p27(KIP1). It is anticipated that a better understanding of this critical intersection between SCFAs, HDACs, and cell cycle control will lead to the design of novel treatment strategies for neoplasias. This review will summarize some of the recent research in these arenas of HDAC-directed cancer therapy and discuss the potential application of these agents in synergy with current chemotherapeutics.
Butyrate, a non-toxic short-chain fatty acid (SCFA) and inhibitor of histone deacetylase (HDAC), has potential as an anti-tumor agent because it imposes a reversible G1 block in normal cells yet induces apoptosis in tumor lines. As a potent reactivator of fetal globin transcription, butyrate is used clinically in the treatment of hemoglobinopathies. The anti-proliferative effect of butyrate and its derivatives on in vivo erythroid cell maturation, however, has limited their utility. The molecular mechanisms underlying the G1 arrest induced by butyrate and related SCFAs remain unclear. One model, drawing on tumor cell data, proposes that HDAC inhibition and subsequent transcriptional induction of cyclin-dependent kinase inhibitor (CKI) p21CIP are required. However, because of potentially confounding genetic mutations present in tumor models, we examined SCFA effects on CKIs in a non-transformed growth control model. Using murine 3T3 fibroblasts, we find p27KIP1 is also strongly induced. Unlike previously described effects of butyrate and HDAC inhibition on p21CIP, p27KIP1 induction did not occur at the transcriptional level; instead, the stability of the p27KIP1 protein increased. Other structurally unrelated HDAC inhibitors, including trichostatin A (TSA), induced p27KIP1 similarly. p27KIP1 was found in cyclin E/Cdk2 complexes, concomitant with suppression of cdk2 activity. Elevation of p27KIP1 is required for the observed G1 blockade, as p27KIP1-deficient fibroblasts were resistant to HDAC inhibition-induced arrest. These data suggest a novel activity for HDAC inhibitors and demonstrate a critical role for p27KIP1 in mediating G1 arrest in response to these drugs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.