RUNX3 Attenuates β-Catenin/T Cell Factors in Intestinal Tumorigenesis

Ito, Kazuhiro; Lim, Agnes; Salto–Tellez, Manuel; Motoda, Lena; Osato, Motomi; Chuang, Linda Shyue Huey; Lee, C.W.L.; Voon, Dc-C; Koo, Jason Kin Wai; Wang, H.; Fukamachi, Hiroshi; Ito, Yoshiaki

doi:10.1016/j.ccr.2009.02.002

Cited by 58 publications

(88 citation statements)

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“…Among these is RUNX3 that codes for runt-related transcription factor 3, which modulates both the transforming growth factor (TGF)-β [81] and the Wnt/β-catenin signaling pathways [82]. Runx3 –/– mice exhibit gastric epithelial proliferation due to decreased apoptosis and reduced sensitivity to the growth inhibitory cytokine, TGF-β.…”

Section: Dna Methylationmentioning

confidence: 99%

“…Thus, suppression of RUNX3 expression leads to aberrant signaling of both pathways, which are commonly dysregulated in colonic carcinogenesis. Loss of function of RUNX3 has significant and constitutive effects on the expression of its target genes, which may then contribute to CRC development [76, 82]. Decreased expression of RUNX3 mRNA due to epigenetic hypermethylation of the RUNX3 promoter occurs in a range of human CRC cell lines [84].…”

Section: Dna Methylationmentioning

confidence: 99%

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Microbiota impact on the epigenetic regulation of colorectal cancer

Yang

Owen

Lightfoot

et al. 2013

Trends in Molecular Medicine

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Mechanisms of colorectal cancer (CRC) development can be roughly divided into three categories: genetic, epigenetic, and aberrant immunologic signaling pathways, all of which may be triggered by an imbalanced intestinal microbiota. Aberrant gut microbial composition, termed “dysbiosis”, has been reported in inflammatory bowel disease patients who are at increased risk for CRC development. Recent studies indicate that it is feasible to rescue experimental models of colonic cancer by oral treatment with genetically engineered beneficial bacteria and/or their immune-regulating gene products. Here, we review the mechanisms of epigenetic modulation implicated in the development and progression of CRC, which may be the result of dysbiosis, and therefore, may be amenable to therapeutic intervention.

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Section: Dna Methylationmentioning

confidence: 99%

Section: Dna Methylationmentioning

confidence: 99%

Microbiota impact on the epigenetic regulation of colorectal cancer

Yang

Owen

Lightfoot

et al. 2013

Trends in Molecular Medicine

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“…The role of RUNX3 in melanoma progression is not known but may follow similar mechanistic pathways as found in other cancers. A recent study has found that RUNX3 forms a ternary complex with β-catenin/TCF4 and attenuates Wnt signaling (40), which is known to play an important role in melanoma progression (41). …”

Section: Discussionmentioning

confidence: 99%

Regulation of RUNX3 Tumor Suppressor Gene Expression in Cutaneous Melanoma

Kitago

Martinez

Nakamura

et al. 2009

Clinical Cancer Research

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Purpose: RUNX3 is a known tumor suppressor gene in several carcinomas. Aberration in RUNX3 expression has not been described for cutaneous melanoma. Therefore, we assessed the expression of RUNX3 in cutaneous melanoma and its regulatory mechanisms relative to tumor progression. Experimental Design: The expression of RUNX3 mRNA and miR-532-5p (microRNA) was assessed in melanoma lines and in primary and metastatic melanoma tumors. Results: RUNX3 mRNA expression was down-regulated in 11 of 11 (100 %) metastatic melanoma lines relative to normal melanocytes (P < 0.001). Among 123 primary and metastatic melanoma tumors and 12 normal skin samples, RUNX3 expression was significantly down-regulated in primary melanomas (n = 82; P = 0.02) and in melanoma metastasis (n = 41; P < 0.0001) versus normal skin (n = 12). This suggested that RUNX3 down-regulation may play a role in the development and progression of melanoma. RUNX3 promoter region hypermethylation was assessed as a possible regulator of RUNX3 expression using methylation-specific PCR. Assessment of RUNX3 promoter region methylation showed that only 5 of 17 (29%) melanoma lines, 2 of 52 (4%) primary melanomas, and 5 of 30 (17%) metastatic melanomas had hypermethylation of the promoter region. A microRNA (miR-532-5p) was identified as a target of RUNX3 mRNA sequences. miR-532-5p expression was shown to be significantly up-regulated in melanoma lines and metastatic melanoma tumors relative to normal melanocytes and primary melanomas, respectively. To investigate the relation between RUNX3 and miR-532-5p, anti^miR-532-5p was transfected into melanoma lines. Inhibition of miR-532-5p up-regulated both RUNX3 mRNA and protein expression. Conclusions: RUNX3 is down-regulated during melanoma progression and miR-532-5p is a regulatory factor of RUNX3 expression.The prognosis for patients with American Joint Committee on Cancer (AJCC) stage I/II melanoma is excellent, with an average 10-year survival rate of 85% (1). However, as melanoma progresses from localized to metastatic disease, survival drops significantly. The 10-year survival rate for AJCC stage IV disease is less than 10% (1). A better understanding of the regulating factors contributing to melanoma tumor growth, progression, and metastases is needed.Three members of the Runt-related (RUNX) family of genes, RUNX1, RUNX2, and RUNX3 transcription factors, are known as developmental regulators important in the inception and progression of a variety of human cancers and experimentally induced mouse tumors (2 -8). RUNX are transcription factors that are known to function as scaffolds and interact with coregulatory factors often involved in tissue differentiation (9). RUNX proteins are located in the nucleus, whereby downregulation of function has been linked to various cancers (9). Studies have also shown RUNX proteins to regulate gene expression by interacting with chromatin remodeling enzymes (10). RUNX3, in particular, has been shown to be involved in gastric tumor progression. In gastric cancer and other ...

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“…( e ) RUNX3 expression is decreased within mouse gastric mucosa early after infection with H. pylori NCTC11637CagA-positive strain. Immunohistochemistry for RUNX3 was performed as previously described (Ito et al , 2008) on gastric mucosa harvested from INS-GAS mice infected with WT or cagA -deficient NCTC11637 H. pylori strains 48 h after inoculation. Representative staining of RUNX3 is shown for WT (left panel) or cagA -deficient mutant (right panel)-infected mice.…”

Section: Figuresmentioning

confidence: 99%

Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation

et al. 2010

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Chronic infection with cagA-positive Helicobacter pylori is the strongest risk factor for the development of gastric adenocarcinoma. The cagA gene product CagA is injected into gastric epithelial cells and disturbs cellular functions by physically interacting with and deregulating a variety of cellular signaling molecules. RUNX3 is a tumor suppressor in many tissues, and it is frequently inactivated in gastric cancer. In this study, we show that H. pylori infection inactivates the gastric tumor suppressor RUNX3 in a CagA-dependent manner. CagA directly associates with RUNX3 through a specific recognition of the PY motif of RUNX3 by a WW domain of CagA. Deletion of the WW domains of CagA or mutation of the PY motif in RUNX3 abolishes the ability of CagA to induce the ubiquitination and degradation of RUNX3, thereby extinguishing its ability to inhibit the transcriptional activation of RUNX3. Our studies identify RUNX3 as a novel cellular target of H. pylori CagA and also reveal a mechanism by which CagA functions as an oncoprotein by blocking the activity of gastric tumor suppressor RUNX3.

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RUNX3 Attenuates β-Catenin/T Cell Factors in Intestinal Tumorigenesis

Cited by 58 publications

References 0 publications

Microbiota impact on the epigenetic regulation of colorectal cancer

Microbiota impact on the epigenetic regulation of colorectal cancer

Regulation of RUNX3 Tumor Suppressor Gene Expression in Cutaneous Melanoma

Helicobacter pylori CagA targets gastric tumor suppressor RUNX3 for proteasome-mediated degradation

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