YB-1 Transforms Human Mammary Epithelial Cells Through Chromatin Remodeling Leading to the Development of Basal-Like Breast Cancer

Davies, Alastair; Reipas, Kristen M.; Pambid, Mary Rose; Berns, Rachel; Stratford, Anna L.; Fotovati, Abbas; Firmino, Natalie; Astanehe, Arezoo; Hu, Kaiji; Maxwell, Christopher A.; Mills, Gordon B.; Dunn, Sandra E.

doi:10.1002/stem.1707

Cited by 39 publications

(47 citation statements)

References 55 publications

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“…It was later discovered that YB-1 induces cytokinesis failure in human mammary epithelial cells, thereby promoting numerical CA, but also limits centrosome size, thereby restraining abnormal amplification of centrosome volume. It additionally induces aneuploidy, dicentric chromosomes and double minutes, extensive chromosome breakage, defective sister chromatid cohesion, and HER amplification (Davies, et al 2011), although a subsequent study found that YB-1 induces triple-negative mammary tumor formation (Davies, et al 2014). Although YB-1 induces numerical CA, it also promotes extensive chromatin remodeling and the development of stem-like properties (Davies et al 2014), and it binds to the promoter of various genes that drive proliferation (e.g., the genes encoding EGFR, HER2, cyclin A, and cyclin B1) (Davies et al 2011), so the relative contribution of CA to YB-1-induced breast tumorigenesis is hard to decipher from this study alone.…”

Section: Centrosome Amplification and Breast Tumorigenesismentioning

confidence: 99%

Centrosome amplification: a suspect in breast cancer and racial disparities

Ogden

Rida

Aneja

2017

Endocrine-Related Cancer

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The multifaceted involvement of centrosome amplification (CA) in tumorigenesis is coming into focus following years of meticulous experimentation, which have elucidated the powerful abilities of CA to promote cellular invasion, disrupt stem cell division, drive chromosomal instability (CIN), and perturb tissue architecture, activities that can accelerate tumor progression. Integration of the extant in vitro, in vivo, and clinical data suggests that in some tissues CA may be a tumor-initiating event, in others a consequential “hit” in multistep tumorigenesis, and in still others non-tumorigenic. However, in vivo data are limited, do not specifically include breast models, and primarily focus on PLK4 (which has CA-independent mechanisms by which it promotes aggressive cellular phenotypes). In vitro breast cancer models suggest that CA can promote tumorigenesis in breast cancer cells in the setting of p53 loss or mutation, which can both trigger CA and promote cellular tolerance to its tendency to slow proliferation and induce aneuploidy. It is thus our perspective that CA is likely an early hit in multistep breast tumorigenesis that may sometimes be lost to preserve aggressive karyotypes acquired through centrosome clustering-mediated CIN, both numerical and structural. We also envision that the robust link between p53 and CA may underlie, to a considerable degree, racial health disparity in breast cancer outcomes. This question is clinically significant because, if it is true, then analysis of centrosomal profiles and administration of centrosome declustering drugs could prove highly efficacious in risk stratifying breast cancers and treating African American (AA) women with breast cancer.

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Section: Centrosome Amplification and Breast Tumorigenesismentioning

confidence: 99%

Centrosome amplification: a suspect in breast cancer and racial disparities

Ogden

Rida

Aneja

2017

Endocrine-Related Cancer

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“…YB-1 overexpressed cells were seen to have phenotypic changes such as formation of acini with lumen along with the expression of tumor initiation cell markers i.e. CD44, CD49f and BMI1 were expressed in earlier YB-1 overexpressed luminal cells (Davies et al, 2014).…”

Section: Yb-1 and Breast Cancermentioning

confidence: 99%

“…A comparative in vitro study on Tet-repressed YB-1 (HTRY) human mammary epithelial cells (HMECs) expressing YB-1 and Tet-repressed Lac-Z (HTRZ) LacZexpressing control cell line showed an up-regulated YB-1 in HTRY cell lines as compared to HTRZ cell lines (Davies et al 2014). The study was conducted to study the transformation of human mammary epithelial cells into BLBC.…”

Section: Yb-1 and Breast Cancermentioning

confidence: 99%

“…These cells were characterized as tumorigenic and basal like breast cancer cells. p300-mediated acetylation of 9 th lysine residue (H3K9) on histone protein triggering effects resulted in BMI1, CD44 and CD49f overexpression in HMECs ( Figure 2) (Davies et al, 2014). CDKN2A/ p16INK4a is a CDK4 kinase inhibitor (Ichimura et al, 1996).…”

Section: Yb-1 and Breast Cancermentioning

confidence: 99%

“…BMI1 induction results in histone H2A ubiquitylation and repression of CDKN2A (cyclin-dependent kinase inhibitor 2A) locus which is responsible for CDK4 kinase inhibition hence, p16 INK4a mediated cell arrest inhibition. This consequently results in self-renewal and development of BLBC (Davies et al, 2014) expression of VEGF is associated with CXCR4 expression. CXCR4 has been shown to up-regulate the phosphorylation of Akt and increased VEGF expression.…”

Section: Yb-1 and Ovarian Cancermentioning

confidence: 99%

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Nuclear shuttling of Y Box binding protein-1, its clinical relevance in cancer and as a therapeutic target

Gunasekaran

Nishi

Ravikumar

et al. 2016

Bangladesh J Pharmacol

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Y-box binding protein 1 (YB-1) is an imperative biomarker for the clinical outcome of cancer patients. An overexpression of YB-1 in cancerous and adjoining tissues is an indication of aggressiveness and advanced stages. In normal resting cells, YB-1 is localized in cytoplasm while in stress conditions like cancer, nuclear shuttling of YB-1 takes place. In this review, the clinical importance of YB-1 in different cancers and the mechanism behind YB-1 nuclear shuttling have been discussed in detail. Targeted chemotherapies or molecularly targeted drugs of great importance can target and block specific molecules implicated in tumor growth and progression. YB-1 has been considered as a bonafide oncogene and accumulating evidences show the therapeutic importance of YB-1. Therapeutic strategies targeting YB-1 may improve the survival rate in cancer patients. This review extensively discusses the therapeutic importance of YB-1. Article InfoReceived:16 Mini-reviewThis article was downloaded by you on: Apr 30, 2016 In normal resting cells, full length YB-1 is mainly present in the cytoplasm of cells under stress during pathological conditions including inflammation, oxidative stress and cancer conditions. Particular segment of the YB-1 flips to the nucleus (Koike et al., 1997;Higashi et al., 2011).In this review, with the nuclear shuttling, clinical significance of YB-1 in cancer and as a therapeutic target have been evaluated from the existing literature. The present literature analysis shows the prospective role of YB-1 in cancer progression and drug resistance which could be harnessed to make it a promising therapeutic target. Nuclear shuttling of YB-1Since a number of functions have been assigned to YB-1, therefore, the sub-cellular protein shuttling needs to be highly stringent. In general, specific nuclear export signals and nuclear localization signals (NLS) contribute and direct the multifunctional shuttling and tasking (Bader and Vogt, 2005). Literature suggests three nuclear localization signals in YB-1 i.e. NLS1 (aa149-55), NLS2 (aa185-94) and NLS3 (276-92) (van Roeyen et al., 2013). The NLS3 is bipartite in composition and both the parts are essential for functionality. Irrespective of this, the changes of the spatial organization of 2 parts doesn't affect nuclear shuttling. Both NLS2 and NLS3 are essential for functionality and contain tyrosine residues which are required for phosphorylation. The full length YB-1 phosphorylated at tyrosine 281 in NLS3 has been found to be localized in the nucleus while the unphosphorylated YB-1 localized in the cytoplasm. This indicates that the phosphorylation at T-281 renders complete YB-1 to be localized in nucleus under normal conditions (van Roeyen et al., 2013). At the time of stress or cell stimulation, nuclear flipping of shortened YB-1 having N-terminal portion of the proteins takes place through a highly regulated process (Bader and Vogt, 2005;van Roeyen et al., 2013). Jürchott et al. (2003) suggested that the both C-terminal and cold shock domain of YB...

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KMT2D‐mediated H3K4me1 recruits YBX1 to facilitate triple‐negative breast cancer progression through epigenetic activation of c‐Myc

Yao,

Xing,

Zeng

et al. 2024

Clinical & Translational Med

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BackgroundLysine methyltransferase 2D (KMT2D) mediates mono‐methylation of histone H3 lysine 4 (H3K4me1) in mammals. H3K4me1 mark is involved in establishing an active chromatin structure to promote gene transcription. However, the precise molecular mechanism underlying the KMT2D‐mediated H3K4me1 mark modulates gene expression in triple‐negative breast cancer (TNBC) progression is unresolved.Methods and ResultsWe recognized Y‐box‐binding protein 1 (YBX1) as a “reader” of the H3K4me1 mark, and a point mutation of YBX1 (E121A) disrupted this interaction. We found that KMT2D and YBX1 cooperatively promoted cell growth and metastasis of TNBC cells in vitro and in vivo. The expression levels of KMT2D and YBX1 were both upregulated in tumour tissues and correlated with poor prognosis for breast cancer patients. Combined analyses of ChIP‐seq and RNA‐seq data indicated that YBX1 was co‐localized with KMT2D‐mediated H3K4me1 in the promoter regions of c‐Myc and SENP1, thereby activating their expressions in TNBC cells. Moreover, we demonstrated that YBX1 activated the expressions of c‐Myc and SENP1 in a KMT2D‐dependent manner.ConclusionOur results suggest that KMT2D‐mediated H3K4me1 recruits YBX1 to facilitate TNBC progression through epigenetic activation of c‐Myc and SENP1. These results together unveil a crucial interplay between histone mark and gene regulation in TNBC progression, thus providing novel insights into targeting the KMT2D‐H3K4me1‐YBX1 axis for TNBC treatment.Highlights YBX1 is a KMT2D‐mediated H3K4me1‐binding effector protein and mutation of YBX1 (E121A) disrupts its binding to H3K4me1. KMT2D and YBX1 cooperatively promote TNBC proliferation and metastasis by activating c‐Myc and SENP1 expression in vitro and in vivo. YBX1 is colocalized with H3K4me1 in the c‐Myc and SENP1 promoter regions in TNBC cells and increased YBX1 expression predicts a poor prognosis in breast cancer patients.

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YB-1 Transforms Human Mammary Epithelial Cells Through Chromatin Remodeling Leading to the Development of Basal-Like Breast Cancer

Cited by 39 publications

References 55 publications

Centrosome amplification: a suspect in breast cancer and racial disparities

Centrosome amplification: a suspect in breast cancer and racial disparities

Nuclear shuttling of Y Box binding protein-1, its clinical relevance in cancer and as a therapeutic target

KMT2D‐mediated H3K4me1 recruits YBX1 to facilitate triple‐negative breast cancer progression through epigenetic activation of c‐Myc

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