Frequent Alteration of XAF1 in Human Colorectal Cancers: Implication for Tumor Cell Resistance to Apoptotic Stresses

Chung, Sun‐Ku; Lee, Min–Goo; Ryu, Byung–Kyu; Lee, Jin–Hee; Han, Jikhyon; Byun, Do-Sun; Chae, Kwon‐Seok; Lee, Kil Yeon; Jang, Jun‐Bock; Kim, Hyo‐Jong; Chi, Sung–Gil

doi:10.1053/j.gastro.2007.04.024

Cited by 60 publications

(91 citation statements)

References 34 publications

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“…with ZKSCAN3 promotes malignant progression in breast cancer (30), although, paradoxically, it reduces tumorigenicity of colon cancer (31). Overexpression of the zinc finger protein ZNF148, sharing 26% similarity with ZKSCAN3 in Min mice, attenuated intestinal tumor development (23); these results resemble XAF1, another tandem zinc finger repeat protein sharing 17% similarity with ZKSCAN3, which suppresses tumor growth and enhances the apoptotic response to a variety of agents (24). In contrast, and like ZKSCAN3, some zinc finger-bearing proteins augment tumorigenicity.…”

Section: Discussionmentioning

confidence: 99%

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The Previously Undescribed ZKSCAN3 (ZNF306) Is a Novel “Driver” of Colorectal Cancer Progression

Yang¹,

Hamilton²,

Sood

et al. 2008

Cancer Research

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A relatively new view of colorectal cancer is that its development/progression reflects the contribution of a large set of altered gene products in varying combinations, each providing a ''fitness advantage.'' In searching for novel contributing gene products using Unigene cluster data mining, we found overrepresentation of expressed sequence tags corresponding to a previously uncharacterized gene (ZKSCAN3) in colorectal tumors. ZKSCAN3 was pursued for several reasons: (a) its sequence similarity with bowl required for Drosophila hindgut development; (b) it lies in a chromosomal region (6p22.1) amplified in colorectal cancer; and (c) its coding sequence predicts tandem C 2 H 2 zinc finger domains present in a class of proteins gaining attention for their role in oncogenesis/tumor progression. Reverse transcription-PCR confirmed overexpression in colorectal tumor tissue compared with adjacent nonmalignant mucosa due in part to gene amplification determined by Southern blotting. Further, immunohistochemistry with an antibody generated to the predicted protein sequence revealed higher ZKSCAN3 expression in invasive compared with noninvasive tumors. Intriguingly, the ZKSCAN3 protein was also expressed in tumors wild-type for genes (APC, p53, K-Ras) commonly targeted in colorectal cancer. ZKSCAN3 knockdown in two independent colon cancer cell lines impaired anchorageindependent growth and orthotopic tumor growth, whereas overexpression in a third cell line had the opposite effect and increased 5-fluorouracil resistance. Liposomal delivery of a ZKSCAN3-targeting small interfering RNA reduced tumorigenicity of orthotopic colon cancer. Thus, the hitherto uncharacterized ZKSCAN3 adds to an expanding set of encoded products contributing to the progression of colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

“…) with the bowl gene required for Drosophila hindgut (precursor of the large intestine) elongation (17); and (c) the coding sequence predicts tandem C 2 H 2 zinc finger domains present in a class of proteins gaining attention for their role in oncogenesis/tumor progression (23)(24)(25).…”

Section: à33mentioning

confidence: 99%

The Previously Undescribed ZKSCAN3 (ZNF306) Is a Novel “Driver” of Colorectal Cancer Progression

Yang¹,

Hamilton²,

Sood

et al. 2008

Cancer Research

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“…17,[31][32][33][34] Epigenetic silencing of the XAF1 gene by aberrant promoter methylation appears to correlate with the malignant progression of human gastric tumors. 18,33 In our study, we demonstrate that overexpression of XAF1 suppressed anchorage-dependent and -independent growth.…”

Section: Discussionmentioning

confidence: 99%

Restoration of XAF1 expression induces apoptosis and inhibits tumor growth in gastric cancer

Liston

Cui

et al. 2009

Intl Journal of Cancer

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XAF1 (XIAP-associated factor 1) is a novel XIAP binding protein that can antagonize XIAP and sensitize cells to other cell death triggers. Our previous results have shown that aberrant hypermethylation of the CpG sites in XAF1 promoter is strongly associated with lower expression of XAF1 in gastric cancers. In our study, we investigated the effect of restoration of XAF1 expression on growth of gastric cancers. We found that the restoration of XAF1 expression suppressed anchorage-dependent and -independent growth and increased sensitivity to TRAIL and druginduced apoptosis. Stable cell clones expressing XAF1 exhibited delayed tumor initiation in nude mice. Restoration of XAF1 expression mediated by adenovirus vector greatly increased apoptosis in gastric cancer cell lines in a time-and dose-dependent manner and sensitized cancer cells to TRAIL and drugs-induced apoptosis. Adeno-XAF1 transduction induced cell cycle G2/M arrest and upregulated the expression of p21 and downregulated the expression of cyclin B1 and cdc2. Notably, adeno-XAF1 treatment significantly inhibited tumor growth, strongly enhanced the antitumor activity of TRAIL in a gastric cancer xenograft model in vivo, and significantly prolonged the survival time of animals bearing tumor xenografts. Complete eradication of established tumors was achieved on combined treatment with adeno-XAF1 and TRAIL. Our results document that the restoration of XAF1 inhibits gastric tumorigenesis and tumor growth and that XAF1 is a promising candidate for cancer gene therapy. ' UICCKey words: XAF1; TRAIL; adenovirus; apoptosis; tumorigenesis; cell cycle arrest; gastric cancer; gene therapy The development of cancer is a result of aberrant cellular proliferation and failure of these cells to undergo apoptosis in response to normal signaling cues. 1 Dysregulation of cell death pathways has been termed a 'hallmarkÕ of cancer 2 and is required for tumor initiation, progression and drug resistance. 3,4 Virtually all known apoptosis signal pathways converge on the caspases. 5 The inhibitor of apoptosis (IAP) genes encode a family of proteins that bind and inactivate key caspases involved in the initiation (Caspase-9) and execution (Caspase-3 and -7) of this cascade. 6 An elevated expression level of XIAP, the most potent of the mammalian IAPs, is associated with tumor resistance to cell death cues. 7,8 Thus the strategies that target XIAP synthesis or function are under investigation for the treatment of cancer. 9 Both antisense 10,11 and small molecule inhibitors of XIAP function 12,13 have demonstrated promise in animal models of human cancer.XAF1 has been previously identified as a XIAP binding partner. 13 XAF1 directly interacts with endogenous XIAP and results in XIAP sequestration in nuclear inclusions. XAF1 antagonizes the anticaspase activity of XIAP and reverses the protective effect of XIAP overexpression in cell lines. 13 XAF1 does not contain an amino terminal tetrapeptide motif analogous to Smac/DIABLO or Omi, suggesting that its mechanism of IAP interaction ...

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“…RNA extraction, cDNA synthesis, and quantitative PCR were carried out as described previously (3,26). Reverse transcriptase PCR (RT-PCR) for PRKCDBP expression was carried out with primers SRBC-4 (sense 5 0 -TTCTGCTCTT-CAAGGAGGAG-3 0 ) and SRBC-7 (antisense 5 0 -CCAAGGC-GAGGCGGCTTGAC-3 0 ).…”

Section: Expression Analysismentioning

confidence: 99%

Epigenetic Alteration of PRKCDBP in Colorectal Cancers and Its Implication in Tumor Cell Resistance to TNFα-Induced Apoptosis

Lee

Han

et al. 2011

Clinical Cancer Research

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Purpose: PRKCDBP is a putative tumor suppressor in which alteration has been observed in several human cancers. We investigated expression and function of PRKCDBP in colorectal cells and tissues to explore its candidacy as a suppressor in colorectal tumorigenesis.Experimental Design: Expression and methylation status of PRKCDBP and its effect on tumor growth were evaluated. Transcriptional regulation by NF-kB signaling was defined by luciferase reporter and chromatin immunoprecipitation assays.Results: PRKCDBP expression was hardly detectable in 29 of 80 (36%) primary tumors and 11 of 19 (58%) cell lines, and its alteration correlated with tumor stage and grade. Promoter hypermethylation was commonly found in cancers. PRKCDBP expression induced the G 1 cell-cycle arrest and increased cellular sensitivity to various apoptotic stresses. PRKCDBP was induced by TNFa, and its level correlated with tumor cell sensitivity to TNFa-induced apoptosis. PRKCDBP induction by TNFa was disrupted by blocking NF-kB signaling while it was enhanced by RelA transfection. The PRKCDBP promoter activity was increased in response to TNFa, and this response was abolished by disruption of a kB site in the promoter. PRKCDBP delayed the formation and growth of xenograft tumors and improved tumor response to TNFa-induced apoptosis.Conclusions: PRKCDBP is a proapoptotic tumor suppressor which is commonly altered in colorectal cancer by promoter hypermethylation, and its gene transcription is directly activated by NF-kB in response to TNFa. This suggests that PRKCDBP inactivation may contribute to tumor progression by reducing cellular sensitivity to TNFa and other stresses, particularly under chronic inflammatory microenvironment. Clin Cancer Res; 17(24); 7551-62. Ó2011 AACR.

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Frequent Alteration of XAF1 in Human Colorectal Cancers: Implication for Tumor Cell Resistance to Apoptotic Stresses

Cited by 60 publications

References 34 publications

The Previously Undescribed ZKSCAN3 (ZNF306) Is a Novel “Driver” of Colorectal Cancer Progression

The Previously Undescribed ZKSCAN3 (ZNF306) Is a Novel “Driver” of Colorectal Cancer Progression

Restoration of XAF1 expression induces apoptosis and inhibits tumor growth in gastric cancer

Epigenetic Alteration of PRKCDBP in Colorectal Cancers and Its Implication in Tumor Cell Resistance to TNFα-Induced Apoptosis

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