Nuclear E-Cadherin Acetylation Promotes Colorectal Tumorigenesis via Enhancing β-Catenin Activity

Zhao, Yongxu; Yu, Tao; Zhang, Nan; Chen, Jianxia; Zhang, Peng; Li, Shuang; Luo, Lijun; Cui, Zhenling; Qin, Yue; Liu, Feng

doi:10.1158/1541-7786.mcr-18-0637

Cited by 24 publications

(27 citation statements)

References 54 publications

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“…The E-cadherin/β-catenin pathway, therefore, has been proposed to be a potential target for cancer therapy because of its role in regulating genes or mediators involved in cancer development and progression [ 42 – 44 ]. In a related finding, Zhao et al demonstrated the involvement of the E-cadherin/β-catenin pathway activation in CRC development [ 45 ]. As an interpretation, these results suggest that an inhibitor of the E-cadherin/β-catenin pathway may be used to potentially treat Fusobacterium nucleatum -related CRC.…”

Section: Discussionmentioning

confidence: 99%

FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2

Guo

Tian

Kong

et al. 2020

J Exp Clin Cancer Res

109

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Background Globally, colorectal cancer (CRC) affects more than 1 million people each year. In addition to non-modifiable and other environmental risk factors, Fusobacterium nucleatum infection has been linked to CRC recently. In this study, we explored mechanisms underlying the role of Fusobacterium nucleatum infection in the progression of CRC in a mouse model. Methods C57BL/6 J-Adenomatous polyposis coli (APC) Min/J mice [APC (Min/+)] were treated with Fusobacterium nucleatum (109 cfu/mL, 0.2 mL/time/day, i.g., 12 weeks), saline, or FadA knockout (FadA−/−) Fusobacterium nucleatum. The number, size, and weight of CRC tumors were determined in isolated tumor masses. The human CRC cell lines HCT29 and HT116 were treated with lentiviral vectors overexpressing chk2 or silencing β-catenin. DNA damage was determined by Comet assay and γH2AX immunofluorescence assay and flow cytometry. The mRNA expression of chk2 was determined by RT-qPCR. Protein expression of FadA, E-cadherin, β-catenin, and chk2 were determined by Western blot analysis. Results Fusobacterium nucleatum treatment promoted DNA damage in CRC in APC (Min/+) mice. Fusobacterium nucleatum also increased the number of CRC cells that were in the S phase of the cell cycle. FadA−/− reduced tumor number, size, and burden in vivo. FadA−/− also reduced DNA damage, cell proliferation, expression of E-cadherin and chk2, and cells in the S phase. Chk2 overexpression elevated DNA damage and tumor growth in APC (Min/+) mice. Conclusions In conclusion, this study provided evidence that Fusobacterium nucleatum induced DNA damage and cell growth in CRC through FadA-dependent activation of the E-cadherin/β-catenin pathway, leading to up-regulation of chk2.

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Section: Discussionmentioning

confidence: 99%

FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2

Guo

Tian

Kong

et al. 2020

J Exp Clin Cancer Res

109

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“…42,43 In contrast, SIRT2 inhibition of Wnt/b-catenin has been shown in certain types of cells. [44][45][46] SIRT2 is a deacetylase of E-cadherin, and acetylation of nuclear E-cadherin attenuates its interaction with b-catenin, which releases bcatenin from the complex, resulting in increased expression of its downstream genes and accelerated tumor growth and migration in colorectal cancer cells. 44 SIRT2 binds to, deacetylates, and activates GSK3b, thereby decreasing b-catenin expression in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

“…[44][45][46] SIRT2 is a deacetylase of E-cadherin, and acetylation of nuclear E-cadherin attenuates its interaction with b-catenin, which releases bcatenin from the complex, resulting in increased expression of its downstream genes and accelerated tumor growth and migration in colorectal cancer cells. 44 SIRT2 binds to, deacetylates, and activates GSK3b, thereby decreasing b-catenin expression in cardiomyocytes. 45 Moreover, SIRT2 knockout results in increased acetylation of b-catenin and activation of the Wnt signaling pathway in mouse embryonic fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation

Zhou

Rychahou

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Using complementary approaches (intestinal epithelial cell lines, intestinal organoids and SIRT2 knockout mice), we demonstrated that SIRT2, decreased in intestinal tissues from patients with inflammatory bowel diseases, contributes to the maintenance of intestinal epithelium homeostasis through regulation of Wnt-b-catenin signaling. BACKGROUND AND AIMS: Intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD). We investigated the role of Sirtuin 2 (SIRT2), a NAD-dependent protein deacetylase, in intestinal epithelial cell (IEC) proliferation and differentiation and the mechanism by which SIRT2 contributes to maintenance of intestinal cell homeostasis. METHODS: IECs were collected from SIRT2-deficient mice and patients with IBD. Expression of SIRT2, differentiation markers (mucin2, intestinal alkaline phosphatase, villin, Na,K-ATPase, and lysozyme) and Wnt target genes (EPHB2, AXIN2, and cyclin D1) was determined by western blot, real-time RT-PCR, or immunohistochemical (IHC) staining. IECs were treated with TNF or transfected with siRNA targeting SIRT2. Proliferation was determined by villus height and crypt depth, and Ki67 and cyclin D1 IHC staining. For studies using organoids, intestinal crypts were isolated. RESULTS: Increased SIRT2 expression was localized to the more differentiated region of the intestine. In contrast, SIRT2 deficiency impaired proliferation and differentiation and altered stemness in the small intestinal epithelium ex vivo and in vivo. SIRT2-deficient mice showed decreased intestinal enterocyte and goblet cell differentiation but increased the Paneth cell lineage and increased proliferation of IECs. Moreover, we found that SIRT2 inhibits Wnt/b-catenin signaling, which critically regulates IEC proliferation and differentiation. Consistent with a distinct role for SIRT2 in maintenance of gut homeostasis, intestinal mucosa from IBD patients exhibited decreased SIRT2 expression. CONCLUSION: We demonstrate that SIRT2, which is decreased in intestinal tissues from IBD patients, regulates Wnt-b-catenin signaling and is important for maintenance of IEC proliferation and differentiation.

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“…It has been reported that CTNND1 is highly phosphorylated and shuttles between the cytoplasm and nucleus where it can interact with transcriptional activators (β-catenin) and repressors (Kaiso) thereby regulating gene expression [ 52 ]. Likewise, CTNND1 is known to be required for nuclear translocation of E-cadherin which in turn regulates β-catenin activity, thereby promoting increased expression of downstream genes and accelerating colorectal tumor growth and migration [ 53 ]. To understand how UPF3A activity contributes to the biology of normal and cancerous colon cells more detailed molecular studies are warranted.…”

Section: Discussionmentioning

confidence: 99%

(Phospho)proteomic Profiling of Microsatellite Unstable CRC Cells Reveals Alterations in Nuclear Signaling and Cholesterol Metabolism Caused by Frameshift Mutation of NMD Regulator UPF3A

Michalak

Katzenmaier

Roeckel

et al. 2020

IJMS

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DNA mismatch repair-deficient colorectal cancers (CRCs) accumulate numerous frameshift mutations at repetitive sequences recognized as microsatellite instability (MSI). When coding mononucleotide repeats (cMNRs) are affected, tumors accumulate frameshift mutations and premature termination codons (PTC) potentially leading to truncated proteins. Nonsense-mediated RNA decay (NMD) can degrade PTC-containing transcripts and protect from such faulty proteins. As it also regulates normal transcripts and cellular physiology, we tested whether NMD genes themselves are targets of MSI frameshift mutations. A high frequency of cMNR frameshift mutations in the UPF3A gene was found in MSI CRC cell lines (67.7%), MSI colorectal adenomas (55%) and carcinomas (63%). In normal colonic crypts, UPF3A expression was restricted to single chromogranin A-positive cells. SILAC-based proteomic analysis of KM12 CRC cells revealed UPF3A-dependent down-regulation of several enzymes involved in cholesterol biosynthesis. Furthermore, reconstituted UPF3A expression caused alterations of 85 phosphosites in 52 phosphoproteins. Most of them (38/52, 73%) reside in nuclear phosphoproteins involved in regulation of gene expression and RNA splicing. Since UPF3A mutations can modulate the (phospho)proteomic signature and expression of enzymes involved in cholesterol metabolism in CRC cells, UPF3A may influence other processes than NMD and loss of UPF3A expression might provide a growth advantage to MSI CRC cells.

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Nuclear E-Cadherin Acetylation Promotes Colorectal Tumorigenesis via Enhancing β-Catenin Activity

Cited by 24 publications

References 54 publications

FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2

FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2

SIRT2 Contributes to the Regulation of Intestinal Cell Proliferation and Differentiation

(Phospho)proteomic Profiling of Microsatellite Unstable CRC Cells Reveals Alterations in Nuclear Signaling and Cholesterol Metabolism Caused by Frameshift Mutation of NMD Regulator UPF3A

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