ARD1 Stabilization of TSC2 Suppresses Tumorigenesis Through the mTOR Signaling Pathway

Kuo, Hsu Ping; Lee, Dung‐Fang; Chen, Chun‐Te; Liu, Mo; Chou, Chao-Kai; Lee, Hong Jen; Du, Yi; Xie, Xiaoming; Wei, Yongkun; Xia, Weiya; Zhang, Weihua; Yang, Jer Yen; Yen, Chia Jui; Huang, Tzu Hsuan; Tan, Minjia; Xing, Gang; Zhao, Yingming; Lin, Chun-Ming; Tsai, Shih Feng; Fidler, Isaiah J.; Hung, Mien‐Chie

doi:10.1126/scisignal.2000590

Cited by 80 publications

(114 citation statements)

References 64 publications

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“…21 Nevertheless, the proposition that hNaa10p is an oncoprotein remains controversial as the opposite effect has also been observed. 22,23 hNaa10p level is reduced in neoplastic thyroid tissue when compared to its non-neoplastic counterpart.…”

Section: Resultsmentioning

confidence: 96%

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Expression of humanNAA11(ARD1B) gene is tissue-specific and is regulated by DNA methylation

et al. 2011

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Section: Resultsmentioning

confidence: 96%

“…23 Increased levels of NAA10 transcripts and hNaa10p proteins were respectively found to correlate with better clinical outcome in breast cancer patients 23 and survival of lung cancer patients. 25 Similar to the yeast Naa10p, mouse Naa10p alone does not display NAT activity.…”

Section: Resultsmentioning

confidence: 99%

Expression of humanNAA11(ARD1B) gene is tissue-specific and is regulated by DNA methylation

et al. 2011

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“…5C). To determine whether ARD1-mediated AR acetylation is ARD1 specific, we generated the catalytically inactive (acetyltransferase null) ARD1 mutant (ARD1 dead) as previously described (14). Expression of the ARD1-dead mutant remarkably reduced the level of acetylated AR (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…By acetylating specific substrate proteins, ARD1 plays important roles in apoptosis, hypoxia, autophagy, and cell proliferation (12)(13)(14)(15). Significantly, recent reports indicate that dysregulation of ARD1 is associated with tumorigenesis in a variety of human cancers including colorectal (16), breast (14), and lung (15,17). However, the role of ARD1 in PCa remains unknown.…”

mentioning

confidence: 99%

Inactivation of androgen-induced regulator ARD1 inhibits androgen receptor acetylation and prostate tumorigenesis

Wang

Guo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Androgen signaling through androgen receptor (AR) is critical for prostate tumorigenesis. Given that AR-mediated gene regulation is enhanced by AR coregulators, inactivation of those coregulators is emerging as a promising therapy for prostate cancer (PCa). Here, we show that the N -acetyltransferase arrest-defect 1 protein (ARD1) functions as a unique AR regulator in PCa cells. ARD1 is up-regulated in human PCa cell lines and primary tumor biopsies. The expression of ARD1 was augmented by treatment with synthetic androgen (R1881) unless AR is deficient or is inhibited by AR-specific siRNA or androgen inhibitor bicalutamide (Casodex). Depletion of ARD1 by shRNA suppressed PCa cell proliferation, anchorage-independent growth, and xenograft tumor formation in SCID mice, suggesting that AR-dependent ARD1 expression is biologically germane. Notably, ARD1 was critical for transcriptionally regulating a number of AR target genes that are involved in prostate tumorigenesis. Furthermore, ARD1 interacted physically with and acetylated the AR protein in vivo and in vitro. Because AR–ARD1 interaction facilitated the AR binding to its targeted promoters for gene transcription, we propose that ARD1 functions as a unique AR regulator and forms a positive feedback loop for AR-dependent prostate tumorigenesis. Disruption of AR–ARD1 interactions may be a potent intervention for androgen-dependent PCa therapy.

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“…Both AKT-and ERK-dependent phosphorylation of TSC2 have been shown to disrupt its interaction with TSC1 and destabilize TSC2 (32,33). Recently, arrest defective protein 1 (ARD1) was shown to acetylate and stabilize TSC2 and loss of heterozygosity (LOH) of ARD1 has been observed in breast, lung, pancreatic, and ovarian cancer samples (34). It is also noteworthy to point out that TSC1 inactivation can lead to TSC2 protein degradation.…”

Section: Discussionmentioning

confidence: 99%

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Huynh

Hao²,

Chan

et al. 2015

Molecular Cancer Therapeutics

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV þ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Mol Cancer Ther; 14(5); 1224-35. Ó2015 AACR.

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ARD1 Stabilization of TSC2 Suppresses Tumorigenesis Through the mTOR Signaling Pathway

Cited by 80 publications

References 64 publications

Expression of humanNAA11(ARD1B) gene is tissue-specific and is regulated by DNA methylation

Expression of humanNAA11(ARD1B) gene is tissue-specific and is regulated by DNA methylation

Inactivation of androgen-induced regulator ARD1 inhibits androgen receptor acetylation and prostate tumorigenesis

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

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