Cell Specific CD44 Expression in Breast Cancer Requires the Interaction of AP-1 and NFκB with a Novel cis-Element

Smith, Shannon M.; Cai, Li

doi:10.1371/journal.pone.0050867

Cited by 36 publications

(24 citation statements)

References 46 publications

(49 reference statements)

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“…We thus suggest that CD44 repression by NF-κB inhibition is via its binding to the CD44 cis -element CR1 [13]. Our previous studies using EMSA, ChIP, and site-directed mutagenesis and reporter assays have confirmed that NF-κB binds with CR1 and represses CD44 expression [13]. Our findings in this study, thus, established a direct correlation with NF-κB inhibition and CD44 repression in breast cancer cells, and provide new insight in the molecular mechanism of CD44 regulation.…”

Section: Discussionmentioning

confidence: 82%

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NF-κB Affects Proliferation and Invasiveness of Breast Cancer Cells by Regulating CD44 Expression

2014

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NF-κB plays an important role in cancer initiation and progression. CD44, a cell surface glycoprotein, is involved in many cellular processes including cell adhesion, migration and proliferation. However, whether and how the two molecules interact in breast cancer is not clear. In recent years, the up-regulation of CD44 has served as a marker for tumor initiating cells in breast cancer and other cancer types. Despite the important role of CD44 in cellular processes and cancer, the mechanism underlying CD44 up-regulation in cancers remains poorly understood. Previously, we have identified a novel cis-element, CR1, located upstream of the CD44 promoter. We demonstrated that NF-κB and AP-1 are key trans-acting factors that interact with CR1. Here, we further analyzed the role of NF-κB in regulating CD44 expression in triple negative breast cancer cells, MDA-MB-231 and SUM159. Inhibition of NF-κB by Bay-11-7082 resulted in a reduction in CD44 expression. CD44 repression via NF-κB inhibition consequently decreased proliferation and invasiveness of breast cancer cells. These findings provide not only new insight into the molecular mechanism underlying CD44 regulation but also potential therapeutic targets that may help eliminate chemo- and radiation-resistant cancer cells.

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Section: Discussionmentioning

confidence: 82%

“…In our recently published study, we have identified an evolutionarily conserved region (CR1) located upstream of the CD44 transcription start site, that functions as a cis- element [13]. We have demonstrated that CR1 has the ability to direct reporter gene expression in a cell-specific manner.…”

Section: Introductionmentioning

confidence: 99%

NF-κB Affects Proliferation and Invasiveness of Breast Cancer Cells by Regulating CD44 Expression

2014

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“…CD44 and ALDH1 are well-known cancer stemness drivers; however, their expression has not been studied in detail. Only a few factors, including STAT3, β-catenin, and NF-kB, have been reported as their transcriptional regulators [60][61][62] . Here, we suggest TSPYL5 as a novel cancer stemness factor that simultaneously activates ALDH1 and CD44 transcription.…”

Section: Discussionmentioning

confidence: 99%

Targeting therapy-resistant lung cancer stem cells via disruption of the AKT/TSPYL5/PTEN positive-feedback loop

Kim

Lee

Kim

et al. 2020

Preprint

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Cancer stem cells (CSCs) are regarded as essential targets to overcome tumor progression and therapeutic resistance; however, practical targeting approaches are limited. Here, we identify testis-specific Y-like protein 5 (TSPYL5) as a CSC-associated factor that promotes stemness and epithelial-to-mesenchymal transition in therapy-resistant non-small cell lung cancer (NSCLC) cells. Aberrantly activated PI3K/AKT pathway in therapy-resistant NSCLC cells promotes TSPYL5 phosphorylation at threonine-120 (pT120), which inhibits ubiquitination and stabilizes TSPYL5. TSPYL5 pT120 also supports SUMOylation, which leads to its nuclear translocation and functions as a transcriptional repressor of PTEN. Nuclear TSPYL5 also activates the transcription of CSC-associated genes, ALDH1 and CD44. Collectively, TSPYL5 pT120 maintains persistent CSC-like characteristics via transcriptional activation of CSC-associated genes and via a positive-feedback loop between the AKT/TSPYL5/PTEN and PTEN/PI3K/AKT signaling pathways. However, inhibition of TSPYL5 pT120 can block aberrant AKT/TSPYL5/PTEN cyclic signaling and cancer stemness. Our study suggests TSPYL5 as a novel target for cancer therapy.

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“…145 , 146 CD44, a unique cell surface glycoprotein, is upregulated in tumor cells. 147 , 148 , 149 Smith et al 150 , 151 have shown that the activity of a cis -acting element, conserved region 1, of CD44 is modulated by NF-κB.…”

Section: Status Of the Upr In Breast Tumorigenesismentioning

confidence: 99%

Implications of aging and the endoplasmic reticulum unfolded protein response on the molecular modality of breast cancer

et al. 2017

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The endoplasmic reticulum (ER) is an important subcellular organelle that is involved in numerous activities required to achieve and maintain functional proteins in addition to its role in the biosynthesis of lipids and as a repository of intracellular Ca2+. The inability of the ER to cope with protein folding beyond its capacity causes disturbances that evoke ER stress. Cells possess molecular mechanisms aimed at clearing unwanted cargo from the ER lumen as an adaptive response, but failing to do so navigates the system towards cell death. This systemic approach is called the unfolded protein response. Aging insults cells through various perturbations in homeostasis that involve curtailing ER function by mitigating the expression of its resident chaperones and enzymes. Here the unfolded protein response (UPR) cannot protect the cell due to the weakening of its protective arm, which exacerbates imbalanced homeostasis. Aging predisposed breast malignancy activates the UPR, but tumor cells maneuver the mechanistic details of the UPR, favoring tumorigenesis and thereby eliciting a treacherous condition. Tumor cells exploit UPR pathways via crosstalk involving various signaling cascades that usher tumor cells to immortality. This review aims to present a collection of data that can delineate the missing links of molecular signatures between aging and breast cancer.

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Cell Specific CD44 Expression in Breast Cancer Requires the Interaction of AP-1 and NFκB with a Novel cis-Element

Cited by 36 publications

References 46 publications

NF-κB Affects Proliferation and Invasiveness of Breast Cancer Cells by Regulating CD44 Expression

NF-κB Affects Proliferation and Invasiveness of Breast Cancer Cells by Regulating CD44 Expression

Targeting therapy-resistant lung cancer stem cells via disruption of the AKT/TSPYL5/PTEN positive-feedback loop

Implications of aging and the endoplasmic reticulum unfolded protein response on the molecular modality of breast cancer

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