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

Abstract

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-alpha-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.

• Authors: Chung-Fan Lee, Derick S-C Ou, Sung-Bau Lee, Liang-Hao Chang, Ruo-Kai Lin, Ying-Shiuan Li, Anup K Upadhyay, Xiaodong Cheng, Yi-Ching Wang, Han-Shui Hsu, Michael Hsiao, Cheng-Wen Wu, Li-Jung Juan
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 120 Issue 8 Pg. 2920-30 (Aug 2010) ISSN: 1558-8238 [Electronic] United States
• PMID: 20592467 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• RNA, Messenger
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases
• DNMT1 protein, human
• Dnmt1 protein, mouse
• Acetyltransferases
• N-Terminal Acetyltransferase A
• NAA10 protein, human
• N-Terminal Acetyltransferase E

Topics

• Acetyltransferases (genetics, physiology)
• Animals
• Cadherins (genetics)
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases (physiology)
• DNA Methylation
• Gene Silencing
• Genes, Tumor Suppressor
• Humans
• Lung Neoplasms (etiology)
• Male
• Mice
• N-Terminal Acetyltransferase A
• N-Terminal Acetyltransferase E
• NIH 3T3 Cells
• Promoter Regions, Genetic
• RNA, Messenger (analysis)