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hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing
Chung-Fan Lee, … , Cheng-Wen Wu, Li-Jung Juan
Chung-Fan Lee, … , Cheng-Wen Wu, Li-Jung Juan
Published July 1, 2010
Citation Information: J Clin Invest. 2010;120(8):2920-2930. https://doi.org/10.1172/JCI42275.
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Research Article Oncology Article has an altmetric score of 13

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

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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-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.

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

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Figure 3

hNaa10p associates with DNMT1 both in vivo and in vitro.

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hNaa10p associates with DNMT1 both in vivo and in vitro.
(A) Co-IP showe...
(A) Co-IP showed that anti-hNaa10p pulled down hNaa10p and DNMT1, but not DNMT3a or DNMT3b, from H1299 cell exacts. (B) Co-IP showed that anti-hNaa10p pulled down hNaa10p and all DNMT1 fragments (V5-tagged) containing aa 291–570 exogenously expressed in H1299 cells, as revealed by Western blot using hNaa10p or V5 Ab. The schematic illustration of DNMT1 fragments used here, and the results of interaction, are summarized above. DMAP, DNMT1-associated protein; PCNA, proliferating cell nuclear antigen; NLS, nuclear localization signal; FTR, replication foci targeting sequence. (C and D) GST pulldown assays showed that the recombinant GST-fused DNMT1 fragments containing aa 291–570 precipitated hNaa10p-V5 in vitro translated from rabbit reticular lysate (C) or His-Xpress-hNaa10p expressed in and purified from E. coli (D), as revealed by Western blot using the respective Abs. In D, lanes 2–4 and 5–7 show results using NP40 and PBS-T, respectively, as incubation/wash buffer. (E) GST-DNMT1 aa 291–570 was used to pull down the in vitro translated V5-tagged hNaa10p mutant lacking aa 102–122 or aa 182–201, or GFP-fused hNaa10p fragments containing aa 1–21, aa 62–81, aa 102–122, or aa 182–201, followed by Western blotting with V5 or GFP Ab. Lanes were run on the same gel but were noncontiguous (white lines).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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