Nonhistone protein acetylation as cancer therapy targets

Abstract

Acetylation and deacetylation are counteracting, post-translational modifications that affect a large number of histone and nonhistone proteins. The significance of histone acetylation in the modification of chromatin structure and dynamics, and thereby gene transcription regulation, has been well recognized. A steadily growing number of nonhistone proteins have been identified as acetylation targets and reversible lysine acetylation in these proteins plays an important role(s) in the regulation of mRNA stability, protein localization and degradation, and protein–protein and protein–DNA interactions. The recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to the transcriptional machinery is a key element in the dynamic regulation of genes controlling cellular proliferation, differentiation and apoptosis. Many nonhistone proteins targeted by acetylation are the products of oncogenes or tumor-suppressor genes and are directly involved in tumorigenesis, tumor progression and metastasis. Aberrant activity of HDACs has been documented in several types of cancers and HDAC inhibitors (HDACi) have been employed for therapeutic purposes. Here we review the published literature in this field and provide updated information on the regulation and function of nonhistone protein acetylation. While concentrating on the molecular mechanism and pathways involved in the addition and removal of the acetyl moiety, therapeutic modalities of HDACi are also discussed.

Keywords::

• acetylation
• cancer therapy
• deacetylation
• epigenetics
• HDAC
• HDAC inhibitor
• histone deacetylase
• nonhistone acetylation

Financial & competing interests disclosure

Shi-Wen Jiang is the Distinguished Cancer Scholar supported by the Georgia Cancer Coalition (GCC). He also serves as a Mayo Collaborative Researcher and receives traveling support from the Department of Obstetrics and Gynecology, Mayo Clinic. This work is partially funded by a grant from the National Institute of Health (NIH R01 HD 41577, Shi-Wen Jiang), NIH/NCI MD Anderson Uterine Cancer SPORE (Jinping Li, Shi-Wen Jiang), Gynecologic Cancer Foundation (GCF; Sean C Dowdy, Shi-Wen Jiang), the Fraternal Order of Eagles Cancer Research Award (Sean C Dowdy, Shi-Wen Jiang), Merck Pharmaceutical Research Funding for Vorinostat Study (Sean C Dowdy, Shi-Wen Jiang), the NIH Clinical Investigator Loan Repayment Program (Sean C Dowdy, Shi-Wen Jiang), the NIH K12 training program (Sean C Dowdy, Shi-Wen Jiang), the Seeding Grant from Mercer University (Jinping Li) and research supplements from the Mercer University School of Medicine (Shi-Wen Jiang). The authors have no other relevant affiliations or financial involvements with any organization or entity with a financial interest in or financial conflict with the subject manner or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.