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

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

研究成果: 雜誌貢獻文章

65 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)2920-2930
頁數11
期刊Journal of Clinical Investigation
120
發行號8
DOIs
出版狀態已發佈 - 八月 2 2010
對外發佈Yes

指紋

Methyltransferases
Gene Silencing
Tumor Suppressor Genes
Carcinogenesis
Cadherins
DNA
Oncogene Proteins
Heterografts
Methylation
Small Interfering RNA
Lung Neoplasms
Catalytic Domain
Neoplasms
Cell Proliferation
Survival
In Vitro Techniques

ASJC Scopus subject areas

  • Medicine(all)

引用此文

hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing. / Lee, Chung-Fan; Ou, Derick S C; Lee, Sung-Bau; Chang, Liang-Hao; Lin, Ruo Kai; Li, Ying-Shiuan; Upadhyay, Anup K.; Cheng, Xiaodong; Wang, Yi-Ching; Hsu, Han-Shui; Hsiao, Michael; Wu, Cheng-Wen; Juan, Li-Jung.

於: Journal of Clinical Investigation, 卷 120, 編號 8, 02.08.2010, p. 2920-2930.

研究成果: 雜誌貢獻文章

Lee, C-F, Ou, DSC, Lee, S-B, Chang, L-H, Lin, RK, Li, Y-S, Upadhyay, AK, Cheng, X, Wang, Y-C, Hsu, H-S, Hsiao, M, Wu, C-W & Juan, L-J 2010, 'hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing', Journal of Clinical Investigation, 卷 120, 編號 8, 頁 2920-2930. https://doi.org/10.1172/JCI42275
Lee, Chung-Fan ; Ou, Derick S C ; Lee, Sung-Bau ; Chang, Liang-Hao ; Lin, Ruo Kai ; Li, Ying-Shiuan ; Upadhyay, Anup K. ; Cheng, Xiaodong ; Wang, Yi-Ching ; Hsu, Han-Shui ; Hsiao, Michael ; Wu, Cheng-Wen ; Juan, Li-Jung. / hNaa10p contributes to tumorigenesis by facilitating DNMT1-mediated tumor suppressor gene silencing. 於: Journal of Clinical Investigation. 2010 ; 卷 120, 編號 8. 頁 2920-2930.
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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.",
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AU - Upadhyay, Anup K.

AU - Cheng, Xiaodong

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AU - Wu, Cheng-Wen

AU - Juan, Li-Jung

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