Hypermethylation-mediated tumor suppressor gene silencing plays a crucial role in tumorigenesis. Understanding its underlying mechanism is essential for cancer treatment. Previous studies on human N-α-acetyltransferase 10, NatA catalytic subunit (hNaa10p; also known as human arrest-defective 1 [hARD1]), have generated conflicting results with regard to its role in tumorigenesis. Here we provide multiple lines of evidence indicating that it is oncogenic. We have shown that hNaa10p overexpression correlated with poor survival of human lung cancer patients. In vitro, enforced expression of hNaa10p was sufficient to cause cellular transformation, and siRNA-mediated depletion of hNaa10p impaired cancer cell proliferation in colony assays and xenograft studies. The oncogenic potential of hNaa10p depended on its interaction with DNA methyltransferase 1 (DNMT1). Mechanistically, hNaa10p positively regulated DNMT1 enzymatic activity by facilitating its binding to DNA in vitro and its recruitment to promoters of tumor suppressor genes, such as E-cadherin, in vivo. Consistent with this, interaction between hNaa10p and DNMT1 was required for E-cadherin silencing through promoter CpG methylation, and E-cadherin repression contributed to the oncogenic effects of hNaa10p. Together, our data not only establish hNaa10p as an oncoprotein, but also reveal that it contributes to oncogenesis through modulation of DNMT1 function.
Chromatin assembly factor 1 contains three subunits, p150, p60, and p48. It is essential for coupling nucleosome assembly to newly synthesized DNA. Whether chromatin assembly factor 1 subunits have functions beyond escorting histones, which depends on the complex formation of p150 and p60, has been an issue of great interest. This study reveals a novel role of p150, but not p60, in gene-specific transcriptional activation. We found that p150 transcriptionally activated an essential viral promoter, the major immediate early promoter (MIEP) of the human cytomegalovirus, independently of p60. Knocking down p150 decreased the MIEP function in both transfected and virally infected cells. The chromatin immunoprecipitation analysis and the in vitro protein-DNA binding assay demonstrated that p150 used its KER domain to associate with the MIEP from ؊593 to ؊574 bp. The N-terminal 244 residues were also found essential for p150-mediated MIEP activation, likely through recruiting the acetyltransferase p300 to acetylate local histones. Domain swapping experiments further showed that the KER and the N terminus of p150 acted as an independent DNA binding and transcriptional activation domain, respectively. Because p60 did not seem involved in the reaction, together these results indicate for the first time that p150 directly activates transcription, independently of its histone deposition function.
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