The Protein Acetyltransferase ARD1: A Novel Cancer Drug Target?

Abstract

Evasion of apoptosis and active cell proliferation are among the characteristics of cancer cells. Triggering the induction of apoptosis or reducing the proliferative rate will potentially be helpful for cancer treatment. Recently, several reports demonstrated that knockdown of the protein acetyltransferase hARD1 significantly reduced the growth rate of human cancer cell lines. Furthermore, hARD1 knockdown induced apoptosis or sensitized cells to drug induced apoptosis. hARD1 acts in complex with the NATH protein and catalyzes cotranslational acetylation of protein N-termini. Thus, it was suggested that the effects on cell proliferation and apoptosis induction are due to a reduced level of N-terminal acetylation of certain substrate proteins. NATH was originally identified as upregulated in thyroid papillary carcinomas and has lately also been found to correlate with aggressiveness and differentiation status of neuroblastic tumours. On the other hand, researchers recently reported that hARD1 acetylates Beta-catenin. Knockdown of hARD1 reduced the transcriptional activity of the Beta-Catenin/TCF4 complex, downregulating cyclin D1 and thereby promoting G1-arrest and inhibition of cell proliferation of lung cancer cells. Although the underlying molecular mechanisms need further clarification, several reports suggest that reduction of hARD1 negatively affects cell growth. Thus, hARD1 or the hARD1-NATH complex stands out as attractive drug targets in cancer treatment. One challenge will be to develop specific inhibitors that discriminate between hARD1 and the many other enzymes, including the histone acetyltransferases, using acetyl-coenzyme A as acetyl donor. This review focuses on the enzymatic and biological activities of hARD1, and potential mechanisms of functional inhibition.

Autoacetylation regulates differentially the roles of ARD1 variants in tumorigenesis

“…The distinct roles of autoacetylated ARD1 variants in regulating tumor growth were investigated under normoxic conditions. Because hARD1 235 promotes cell proliferation (3,26), the effects of the ARD1 variants on cell growth were compared. Cell proliferation was analyzed after HeLa cells were transfected with plasmids for ARD1 variants.…”

hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing

“…Whether high expression of hNaa10p in these cancers contributes to tumorigenesis remains to be investigated. As mentioned in Introduction, whether hNaa10p is an oncoprotein or a tumor suppressor is still debated (36,37). In contrast to the oncogenic role of hNaa10p in lung tumorigenesis, we indeed found that depletion of hNaa10p increased the colony formation ability of MCF7, a breast cancer cell line (data not shown).…”

“…The oncogenic potential of hNaa10p is further supported by its increased protein level in tumor tissues (33)(34)(35). How hNaa10p contributes to tumorigenesis is unclear (36,37). In the current study, we identified that hNaa10p acts as an oncoprotein that represses the expression of tumor suppressor genes by facilitating DNMT1 function.…”

Different subcellular localizations and functions of human ARD1 variants

“…In mammalian cells, ARD1 regulates diverse cellular activities including growth, apoptosis, autophagy and differentiation (7)(8)(9)(10)(11)(12). In particular, ARD1 garnered attention as a molecule that plays a critical role in cancer progression (13)(14)(15). ARD1 expression is elevated in various human cancers such as lung, breast, prostate, thyroid, and colorectal cancer (16)(17)(18)(19)(20).…”