Inhibiting the SUMO Pathway Represses the Cancer Stem Cell Population in Breast and Colorectal Carcinomas

Bogachek, Maria V.; Park, Jung M.; Andrade, James P. De; Lorenzen, Allison W.; Kulak, Mikhail V.; White, Jeffrey R.; Gu, Vivian W.; Wu, Vincent T.; Weigel, Ronald J.

doi:10.1016/j.stemcr.2016.11.001

Cited by 60 publications

(60 citation statements)

References 57 publications

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“…Where they can be compared, the current findings are consistent with previous reports that examined the role of AP-2g in the mouse mammary gland (Cyr et al, 2015;Jager et al, 2010). As noted previously, Igfbp5 was identified as an AP-2g target gene in the mammary gland (Jager et al, 2003) and we noted a significant repression of Igfbp5 expression in basal cluster 4 and luminal cluster 7 (Supplemental Table 1 (Bogachek et al, 2016;Cyr et al, 2015). One likely hypothesis is that AP-2g is necessary for the multipotent MaSCs to generate luminal progenitors, which could explain both the findings in mammary gland development and luminal breast cancer models (Figure 7b).…”

Section: Discussionsupporting

confidence: 91%

AP-2γ is Required for Maintenance of Pluripotent Mammary Stem Cells

Cho

Thompson

et al. 2020

Preprint

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Highlights• AP-2g-deficient mice exhibited repressed ductal outgrowth and regenerative capacity• Loss of AP-2g reduced the number of mammary stem and luminal progenitor cells • AP-2g target genes, including C/EBPb, IkBa, and Rspo1, regulate mammary development • AP-2g is required for maintenance of pluripotent mammary stem cells eTOC blurb Gu, Cho and colleagues utilized a conditional knockout of Tfap2c to examine transcriptional effects of AP-2g on mammary stem cells. Single cell analysis demonstrated that AP-2g-deficient mice have decreased numbers of mammary stem cells and alteration of genes required for mammary development including C/EBPb, IkBa, and Rspo1. They demonstrate that AP-2g is necessary for maintenance of pluripotent mammary stem cells.

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Section: Discussionsupporting

confidence: 91%

AP-2γ is Required for Maintenance of Pluripotent Mammary Stem Cells

Cho

Thompson

et al. 2020

Preprint

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“…While others have reported decreases in protein SUMOylation using ginkgolic/anacardic acid in various models of cancer (e.g. breast, colorectal and pancreatic), the literature lacks reports on the preclinical efficacy of ginkgolic/anacardic acid in GBM 36 , 37 . Incubation of GBM tumour cell lines with ginkgolic acid or anacardic acid did not result in statistically significant decreases in global protein SUMOylation; whether this may be attributed to exceptionally high levels of global SUMOylation in GBM cells of up to ~40-fold of that of normal tissue 18 , the employment of different dosing stratagems and/or some other unique feature of GBM pathobiology remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Topotecan is a potent inhibitor of SUMOylation in glioblastoma multiforme and alters both cellular replication and metabolic programming

Bernstock

Geßler

et al. 2017

Sci Rep

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Protein SUMOylation is a dynamic post-translational modification shown to be involved in a diverse set of physiologic processes throughout the cell. SUMOylation has also been shown to play a role in the pathobiology of myriad cancers, one of which is glioblastoma multiforme (GBM). As such, the clinical significance and therapeutic utility offered via the selective control of global SUMOylation is readily apparent. There are, however, relatively few known/effective inhibitors of global SUMO-conjugation. Herein we describe the identification of topotecan as a novel inhibitor of global SUMOylation. We also provide evidence that inhibition of SUMOylation by topotecan is associated with reduced levels of CDK6 and HIF-1α, as well as pronounced changes in cell cycle progression and cellular metabolism, thereby highlighting its putative role as an adjuvant therapy in defined GBM patient populations.

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“…EMT is regulated by transcription factors including Snai1/2, ZEB1/2, and twist1 [ 11 ], and by multiple signaling pathways including TGFβ, AKT, ERK1/2, Notch, and WNT [ 12 – 15 ]. miRNAs function by negatively regulating the expression of their target genes at the post-transcriptional level through binding to the 3′ untranslated region of target genes.…”

Section: Introductionmentioning

confidence: 99%

miR-203 inhibits ovarian tumor metastasis by targeting BIRC5 and attenuating the TGFβ pathway

Wang

Zhao

et al. 2018

J Exp Clin Cancer Res

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BackgroundWe previously reported that miR-203 functions as a tumor suppressor in ovarian cancer cells by directly targeting transcription factor Snai2 and inhibiting epithelial to mesenchymal transition (EMT), whereas BIRC5/survivin promotes EMT. In this study, we tested our hypothesis that miR-203 inhibits ovarian tumor metastasis by suppressing EMT through targeting BIRC5, using an orthotopic ovarian cancer mouse model.MethodsWe overexpressed miR-203 in ovarian cancer SKOV3 and OVCAR3 cells using a lentiviral vector and examined cell migration and invasion using transwell plates. The small molecule inhibitor, YM155, was used to inhibit survivin expression. miR-203-expressing and control SKOV3 cells were intrabursally injected into immunocompromised NSG female mice. Primary tumors in ovaries and metastatic tumors were collected to determine the expression of survivin and EMT markers using Western blot and immunostaining.ResultsOverexpression of miR-203 inhibits EMT by targeting BIRC5 in ovarian cancer SKOV3 and OVCAR3 cells. miR-203 expression enhances the ability of the survivin inhibitor YM155 to reduce tumor cell migration and invasion in vitro. We further showed that miR-203 expression attenuated the TGFβ pathway in both SKOV3 and OVCAR3 cells. miR-203 expression also inhibited primary tumor growth in ovaries and metastatic tumors in multiple peritoneal organs including liver and spleen.ConclusionmiR-203 inhibits ovarian tumor metastasis by targeting BIRC5/survivin and attenuating the TGFβ pathway.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0906-0) contains supplementary material, which is available to authorized users.

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Inhibiting the SUMO Pathway Represses the Cancer Stem Cell Population in Breast and Colorectal Carcinomas

Cited by 60 publications

References 57 publications

AP-2γ is Required for Maintenance of Pluripotent Mammary Stem Cells

AP-2γ is Required for Maintenance of Pluripotent Mammary Stem Cells

Topotecan is a potent inhibitor of SUMOylation in glioblastoma multiforme and alters both cellular replication and metabolic programming

miR-203 inhibits ovarian tumor metastasis by targeting BIRC5 and attenuating the TGFβ pathway

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