HES1 in immunity and cancer

Rani, Aradhana; Greenlaw, Roseanna; Smith, Richard A.; Galustian, Christine

doi:10.1016/j.cytogfr.2016.03.010

Cited by 61 publications

(56 citation statements)

References 54 publications

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“…Lysosomal degradation has recently been shown to account for NICD3 clearance and the attenuation of NICD3 target gene activation (Jia et al, ). As an important component of the Notch signaling pathway, HES1, which belongs to the highly conserved basic helix‐loop‐helix family of transcription factors and exerts its biological function by binding to N‐boxes (CACNAG), is required for cell proliferation (Rani, Greenlaw, Smith, & Galustian, ), differentiation (Dhanesh, Subashini, & James, ) and liver fibrogenesis (Zhang, Zhang et al, ). In the present study, COS down‐regulated the Notch3–HES1 pathway and the decrease in HES1 expression correlated with the increase in NICD3 monoubiquitination levels and lysosomal degradation.…”

Section: Discussionmentioning

confidence: 99%

Costunolide represses hepatic fibrosis through WW domain‐containing protein 2‐mediated Notch3 degradation

Liu

Zhang

et al. 2019

British J Pharmacology

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Background and Purpose This study investigates the antifibrotic activities and potential mechanisms of costunolide (COS), a natural sesquiterpene compound. Experimental Approach Rats subjected to bile duct ligation and mice challenged with CCl4 were used to study the antifibrotic effects of COS in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX‐2 also served as an in vitro liver fibrosis models. The expression of fibrogenic genes and signaling proteins in the neurogenic locus notch homologue protein 3 (Notch3)–hairy/enhancer of split‐1 (HES1) pathway was examined using western blot and/or real‐time PCR. Notch3 degradation was analysed using immunofluorescence and coimmunoprecipitation. Key Results In animals, COS administration attenuated hepatic histopathological injury and collagen accumulation and reduced the expression of fibrogenic genes. COS time‐ and dose‐dependently suppressed the levels of fibrotic markers in LX‐2 cells and mouse pHSCs. Mechanistic studies showed COS destabilized Notch3 and subsequently inhibited the Notch3–HES1 pathway, thus inhibiting HSC activation. Furthermore, COS blocked the WW domain‐containing protein 2 (WWP2)/protein phosphatase 1G (PPM1G) interaction and enhanced the effect of WWP2 on Notch3 degradation. Conclusions and Implications COS exerted potent antifibrotic effects in vitro and in vivo by disrupting the WWP2/PPM1G complex, promoting Notch3 degradation and inhibiting the Notch3/HES1 pathway. This indicates that COS may be a potential therapeutic candidate for the treatment of liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Costunolide represses hepatic fibrosis through WW domain‐containing protein 2‐mediated Notch3 degradation

Liu

Zhang

et al. 2019

British J Pharmacology

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“…The hairy and enhancer of split (HES) family has seven members, HES1-7, which belong to the basic helix-loop-helix superfamily of DNA-binding transcription factors and directly affect cellular activities (12). Studies have demonstrated that HES1 affects cell proliferation and differentiation during embryogenesis, maintenance of stem cells, and the malignancy and maintenance of tumor cells (13). Overexpression of HES1 is associated with the development of several types of cancer, including lung cancer, cervical cancer, prostate cancer, oral squamous cell carcinoma, pancreatic cancer, colon carcinoma, and ovarian cancer (14)(15)(16).…”

Section: Lutein Inhibits Proliferation Invasion and Migration Of Hypmentioning

confidence: 99%

“…Antitumor effects of lutein are mediated through downregulation of HES1. HES1 is involved in the regulation of cell cycle, growth, differentiation, invasion, and apoptosis in various cancers (12,13). Therefore, the involvement of HES1 in the effects of lutein on tumor inhibition were investigated.…”

Section: Lutein Suppresses the Viability And Induces The Apoptosis Ofmentioning

confidence: 99%

Lutein inhibits proliferation, invasion and migration of hypoxic breast cancer cells via downregulation of HES1

Zhang

Liu

et al. 2018

Int J Oncol

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An intratumoral hypoxic microenvironment is frequently observed in solid tumors, including breast cancer. Lutein, a plant-derived compound and non-vitamin A carotenoid, has been demonstrated to possess multiple protective properties including anti-inflammation, anti-oxidative stress and antitumor effects. The main objective of the present research was to elucidate the involvement of lutein in the production of reactive oxygen species (ROS) under hypoxia, the activation of hairy and enhancer of split 1 (HES1), and the proliferation, invasion and migration of breast cancer cells. The human breast cancer cell lines MDA‑MB‑157 and MCF‑7 were exposed to hypoxic conditions and various concentrations of lutein. An MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was performed to examine cell proliferation, and Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to analyze the apoptosis ratio. The levels of hypoxia inducible factor-1α (HIF‑1α), NOTCH signaling molecules, HES1 and epithelial-mesenchymal transition (EMT)-associated factors were examined by reverse transcription-quantitative polymerase chain reaction and western blot analysis. Wound healing and Transwell invasion assays were used to detect the invasion and migration of breast cancer cells. Intracellular ROS levels were examined using 2,7-dichlorodihydrofluorescein-diacetate and flow cytometry. The results revealed that cell proliferation was inhibited by lutein in a dose-dependent manner, and the apoptosis ratio gradually increased with lutein treatment under hypoxia as evident from flow cytometry-based analysis. Exposure to lutein inhibited hypoxia-mediated activation of HIF‑1α, NOTCH signaling and HES1 expression, and suppressed the hypoxia-induced expression of EMT-associated factors. Lutein markedly inhibited the invasion and migration of breast cancer cells under hypoxia. Hypoxia-induced production of ROS was also decreased by lutein. Furthermore, the ROS scavenger N‑acetylcysteine also suppressed hypoxia inducible factor 1α and HES1 expression in breast cancer cells during hypoxia, but hydrogen peroxide (H2O2) levels were increased. Taken together, the results of the present study suggested that lutein may be a novel candidate for the chemoprevention of breast cancer. Furthermore, HES1 may be crucial in mediating the involvement of lutein in the suppression of hypoxia-driven ROS-induced breast cancer progression.

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“…Hes1 is a transcription factor that represses genes involved in cellular development and is regulated primarily by NOTCH signaling, one of our top ten overlapping hallmark gene sets bookmarked by RUNX1 (Fig. 4)(96, 97). HES1 was recently shown to have a prominent role in proliferation and invasion of breast cancer cells, and its silencing led to downregulation of p-Akt signaling and ultimately prevented EMT (93).…”

Section: Discussionmentioning

confidence: 99%

RUNX1 mitotically bookmarks target genes that are important for the mammary epithelial-to-mesenchymal transition

Rose

Moskovitz

Boyd

et al. 2019

Preprint

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Key Words: Mammary phenotype, epithelial phenotype, RUNX1, mitotic gene 23 bookmarking. 24 25 26 2Significance: 27 This study elucidates mitotic gene bookmarking as a potential epigenetic 28 mechanism that impacts breast epithelial cell growth and phenotype and has potential 29 implications in breast cancer onset. 30 3 ABSTRACT 31RUNX1 has recently been shown to play an important role in determination of 32 mammary epithelial cell identity. However, mechanisms by which loss of the RUNX1 33 transcription factor in mammary epithelial cells leads to epithelial-to-mesenchymal 34 transition (EMT) are not known. Here, we report mitotic bookmarking of genes by RUNX1 35 as a potential mechanism to convey regulatory information through successive cell 36 divisions for coordinate control of mammary cell proliferation, growth, and identity. 37 Genome-wide RUNX1 occupancy profiles for asynchronous, mitotically enriched, and 38 early G1 breast epithelial cells reveal RUNX1 is retained during the mitosis to G1 39 transition on protein coding and long non-coding RNA genes critical for mammary 40 epithelial proliferation, growth, and phenotype maintenance. Disruption of RUNX1 DNA 41 binding and association with mitotic chromosomes alters cell morphology, global protein 42 synthesis, and phenotype-related gene expression. Together, these findings show for the 43 first time that RUNX1 bookmarks a subset of epithelial-related genes during mitosis that 44 remain occupied as cells enter the next cell cycle. Compromising RUNX1 DNA binding 45 initiates EMT, an essential first step in the onset of breast cancer. 46 47 48Breast cancer arises from a series of acquired mutations and epigenetic changes 49 that disrupt normal mammary epithelial homeostasis and create multi-potent cells that 50 can differentiate into biologically unique and clinically distinct subtypes (1-6). Epithelial-51 to-mesenchymal transition (EMT)-a trans-differentiation process through which 52 mammary epithelial cells acquire the aggressive mesenchymal phenotype-is a key 53 driver of breast cancer progression, invasion and metastasis (7-12). Transcription factors 54 Snail, Slug, Twist, and Zeb1/2 contribute to EMT during early, normal development and 55 have also been implicated in invasion (13)(14)(15)(16). Despite accumulating evidence that 56 defines a broad understanding of EMT regulation and maintenance of the epithelial 57 phenotype (7-12), the mechanism(s) by which mammary cells maintain their epithelial 58 phenotype is unknown. 59Runt-Related Transcription Factor 1 (RUNX1/AML1) is required for hematopoietic 60 lineage specification during development and hematopoiesis throughout life (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). In 61 addition to the recognized role in hematological malignancies, RUNX1 has been recently 62 identified as a key player in breast cancer development and tumor progression (31-38). 63Findings from our group (39), reinforced by studies from others (40, 41), have shown that 64 RUNX1 plays a critical role in maintaini...

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HES1 in immunity and cancer

Cited by 61 publications

References 54 publications

Costunolide represses hepatic fibrosis through WW domain‐containing protein 2‐mediated Notch3 degradation

Costunolide represses hepatic fibrosis through WW domain‐containing protein 2‐mediated Notch3 degradation

Lutein inhibits proliferation, invasion and migration of hypoxic breast cancer cells via downregulation of HES1

RUNX1 mitotically bookmarks target genes that are important for the mammary epithelial-to-mesenchymal transition

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