Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors

Xu, Huiling; Yan, Yuqian; Deb, Siddhartha; Rangasamy, Danny; Germann, Markus; Malaterre, Jordane; Eder, Noreen; Ward, Robyn L.; Hawkins, Nicholas J.; Tothill, Richard W.; Chen, Long; Mortensen, Neil; Fox, Stephen B.; McKay, Michael J.; Ramsay, Robert G.

doi:10.1016/j.celrep.2014.10.059

Cited by 43 publications

(39 citation statements)

References 46 publications

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“…Indeed activated Cyclin E1 through its promotion of CIN accelerates LOH (47) with Apc wt LOH having been shown to be a key event in adenoma formation in the Apc Min/þ mouse (48). Indeed, we have recently shown that CIN begins immediately following the loss of the WT allele in Apc Min/þ organoid cultures (49). Furthermore, we observed a decrease in chromosomal abnormalities in CT26 cells, most notably the degree of tetraploidy with Cyclin E1 knockdown.…”

Section: Discussionsupporting

confidence: 51%

Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis

Cheasley

Pereira

Sampurno

et al. 2015

Molecular Cancer Research

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Cyclin E1 is essential for the reentry of quiescent cells into the cell cycle. When hypomorphic mutant Myb mice (Myb Plt4 ) were examined, it was noted that Cyclin E1 (Ccne1) expression was reduced. Furthermore, the induction of Ccne1 in recovering intestinal epithelia following radiation-induced damage was ablated in Myb-mutant mice. These data prompted us to investigate whether Myb directly regulated Ccne1 and to examine whether elevated Myb in colorectal cancer is responsible for Cyclin E1-driven tumor growth. Here, it was found that Myb/ MYB and Ccne1/CCNE1 expressions were coupled in both mouse and human adenomas. In addition, the low molecular weight Cyclin E1 was the predominant form in intestinal crypts and adenomatous polyposis coli (Apc)-mutant adenomas. Chromatin immunoprecipitation (ChIP) analysis confirmed that Myb bound directly to the Ccne1 promoter and regulated its endogenous expression. In contrast, Myb Plt4 served as a dominant-negative factor that inhibited wild-type Myb and this was not apparently compensated for by the transcription factor E2F1 in intestinal epithelial cells. Myb Plt4/Plt4 mice died prematurely on an Apc Min/þ background associated with hematopoietic defects, including a myelodysplasia; nevertheless, Apc Min/þ mice were protected from intestinal tumorigenesis when crossed to Myb Plt4/þ mice. Knockdown of CCNE1 transcript in murine colorectal cancer cells stabilized chromosome ploidy and decreased tumor formation. These data suggest that Cyclin E1 expression is Myb dependent in normal and transformed intestinal epithelial cells, consistent with a cell-cycle progression and chromosome instability role in cancer.Implications: This study demonstrates that Myb regulates Cyclin E1 expression in normal gastrointestinal tract epithelial cells and is required during intestinal tumorigenesis. Mol Cancer Res; 13(8); 1185-96. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 51%

Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis

Cheasley

Pereira

Sampurno

et al. 2015

Molecular Cancer Research

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“…21 In prognostic analyses, SCC1/RAD21 overexpression has been associated with poor prognosis in high-grade luminal, basal, and Her2-amplified breast cancer subgroups. 22 Corresponding results on SCC1/RAD21 overexpression and an unfavorable prognosis have been achieved from human prostate cancer, 23 myeloid malignancies, 24 and colorectal cancer. 22 SMC1 subunit overexpression has been detected in a panel of triple-negative breast cancer cell lines, but not in hormone-receptor-positive breast cancer cells.…”

Section: Discussionmentioning

confidence: 86%

The Expression of Cohesin Subunit SA2 Predicts Breast Cancer Survival

Repo

Löyttyniemi

Nykänen

et al. 2016

Applied Immunohistochemistry &Amp; Molecular Morphology

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Cohesin is one of the main regulators of sister chromatid separation during the metaphase/anaphase transition. It is a multiprotein complex consisting of 4 core subunits, one of those being the SA2 subunit. SA2 plays the final role in dismantling the cohesion complex from the sister chromatids and also functions in DNA double-strand break repair and gene regulation. There is increasing evidence regarding the involvement of both overexpression and underexpression of cohesin in cancer. Here, we present expression patterns of SA2 in different types of human breast tissue, and the prognostic analysis in the material from breast cancer patients with long-term follow-up. SA2 immunoexpression was evaluated in benign, precancerous, and malignant breast tissue, and was classified into low-intensity or high-intensity groups. The DNA content was determined by image cytometry on breast cancer cell imprints. Prognostic analyses were based on 445 breast cancer patients with upto 20 years' follow-up. SA2 immunoexpression was equally high in both benign and precancerous breast tissue. Instead, 72% of the invasive breast cancers showed deficient SA2 expression. These patients were also associated with an unfavorable outcome as indicated by a 1.6-fold risk of breast cancer death (P=0.0208). The majority (75%) of the patients with low SA2 expression were alive 6.0 years after the diagnosis, whereas the majority of the patients with high SA2 expression survived 17.6 years after the diagnosis. No statistically significant association could be detected between SA2 immunoexpression and DNA aneuploidy. Our results and previous literature indicate that decreased SA2 immunoexpression is associated with malignant breast disease and a particularly unfavorable course of disease.

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“…Rad21 is a member of the cohesin family, which is activated by the Wnt/β-catenin pathway. In human CRC cell lines, 87 L1 was found to be activated by Rad21, leading to speculation that L1 activation might be linked to the oncogenic Wnt/β-catenin pathway. Associations between p53 deficiency and L1 expression or hypomethylation were observed in multiple cancers.…”

Section: Perspectives: Implications Of L1 Activity and Expression In mentioning

confidence: 99%

LINE-1 in cancer: multifaceted functions and potential clinical implications

Han

et al. 2016

Genetics in Medicine

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ReviewThe human genome is abundant with interspersed repetitive sequences originated from retrotransposons. Until now, three categories of retrotransposons have remained unequivocally active: LINE-1(L1), Alu, and SVA elements. The first one is autonomous-capable of self-propagation through RNA intermediates-and the latter two are nonautonomous and thus rely on L1 for mobilization. There are approximately 500,000 L1 copies in the human genome, composing 17% of human DNA.

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Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors

Cited by 43 publications

References 46 publications

Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis

Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis

The Expression of Cohesin Subunit SA2 Predicts Breast Cancer Survival

LINE-1 in cancer: multifaceted functions and potential clinical implications

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