Abstract TMEM-034: THE HEAT SHOCK TRANSCRIPTION FACTOR HSF1 INDUCES OVARIAN CANCER EPITHELIAL-MESENCHYMAL TRANSITION IN A 3D SPHEROID GROWTH MODEL

AbstractWe aimed to determine the mechanism of epithelial-mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.Novelty and ImpactThis study provides new insight into molecular mechanisms by which EMT transcription factor SNAI1 exerts its pro-stemness effects in cancer cells, demonstrating its potential as a stem cell-directed target for therapy. In vitro and in vivo, mesoporous silica nanoparticle-mediated SNAI1 knockdown resulted in restoration of let-7 miRNA, inhibiting stemness and reducing tumor burden. Our studies validate in vivo nanoparticle-delivered RNAi targeting the SNAI1/let-7 axis as a clinically relevant approach.

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Upregulation of Bromodomain PHD‑finger transcription factor in ovarian cancer and its critical role for cancer cell proliferation and survival

Biochemistry and Cell Biology ◽

10.1139/bcb-2020-0227 ◽

2020 ◽

Author(s):

Juan Miao ◽

Min Zhang ◽

Xiaohao Huang ◽

Lei Xu ◽

Ranran Tang ◽

...

Keyword(s):

Ovarian Cancer ◽

Cell Proliferation ◽

Transcription Factor ◽

Signaling Pathways ◽

Cell Lines ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Nucleosome Remodeling ◽

Phd Finger ◽

Mesenchymal Transition

Abstract: Bromodomain PHD finger transcription factor (BPTF) is a core subunit of nucleosome-remodeling factor (NURF) complex, which plays an important role in the development of several cancers. However, it is unknown whether BPTF regulates ovarian cancer (OC) progression. Relative expression of BPTF in cell lines and tissues of OC were measured by Western blot and immunohistochemistry respectively. Clinical significance of BPTF in OC was analyzed by Chisquare test. BPTF knockdown effects on the proliferation, migration, invasion and apoptosis of OC cells were examined. Mechanism studies revealed that these effects were achieved through simultaneous modulation of multiple signaling pathways. We found that BPTF was highly expressed in OC cell lines and tissues compared with normal human ovarian epithelial cell and non-cancerous tissues (p<0.05). These results are also supported by the public RNA-seq data. BPTF overexpression was correlated with poor ovarian cancer patient survival (p<0.05). Vitro experiments revealed that the down-regulation of BPTF inhibited OC cell proliferation, colony formation, migration, invasion and induced its apoptosis. BPTF knockdown also regulated the epithelial-mesenchymal transition (EMT) signaling pathways and induced the cleavage of apoptosis-related proteins. Consequently, BPTF plays a critical role in regulating OC cell survival and functions as a potential therapeutic target for OC.

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LIM-homeobox transcription factor 1, alpha (LMX1A) inhibits tumourigenesis, epithelial–mesenchymal transition and stem-like properties of epithelial ovarian cancer

Gynecologic Oncology ◽

10.1016/j.ygyno.2012.12.018 ◽

2013 ◽

Vol 128 (3) ◽

pp. 475-482 ◽

Cited By ~ 20

Author(s):

Tai-Kuang Chao ◽

Yi-Te Yo ◽

Yu-Ping Liao ◽

Yu-Chi Wang ◽

Po-Hsuan Su ◽

...

Keyword(s):

Ovarian Cancer ◽

Transcription Factor ◽

Epithelial Ovarian Cancer ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Homeobox Transcription Factor ◽

Transcription Factor 1

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Activation of the DNA-binding ability of human heat shock transcription factor 1 may involve the transition from an intramolecular to an intermolecular triple-stranded coiled-coil structure.

Molecular and Cellular Biology ◽

10.1128/mcb.14.11.7557 ◽

1994 ◽

Vol 14 (11) ◽

pp. 7557-7568 ◽

Cited By ~ 126

Author(s):

J Zuo ◽

R Baler ◽

G Dahl ◽

R Voellmy

Keyword(s):

Transcription Factor ◽

Heat Stress ◽

Heat Shock ◽

Dna Binding ◽

Hydrophobic Interactions ◽

Coiled Coil ◽

Heat Shock Transcription Factor ◽

Single Amino Acid ◽

Binding Ability ◽

Heat Shock Element

Heat stress regulation of human heat shock genes is mediated by human heat shock transcription factor hHSF1, which contains three 4-3 hydrophobic repeats (LZ1 to LZ3). In unstressed human cells (37 degrees C), hHSF1 appears to be in an inactive, monomeric state that may be maintained through intramolecular interactions stabilized by transient interaction with hsp70. Heat stress (39 to 42 degrees C) disrupts these interactions, and hHSF1 homotrimerizes and acquires heat shock element DNA-binding ability. hHSF1 expressed in Xenopus oocytes also assumes a monomeric, non-DNA-binding state and is converted to a trimeric, DNA-binding form upon exposure of the oocytes to heat shock (35 to 37 degrees C in this organism). Because endogenous HSF DNA-binding activity is low and anti-hHSF1 antibody does not recognize Xenopus HSF, we employed this system for mapping regions in hHSF1 that are required for the maintenance of the monomeric state. The results of mutagenesis analyses strongly suggest that the inactive hHSF1 monomer is stabilized by hydrophobic interactions involving all three leucine zippers which may form a triple-stranded coiled coil. Trimerization may enable the DNA-binding function of hHSF1 by facilitating cooperative binding of monomeric DNA-binding domains to the heat shock element motif. This view is supported by observations that several different LexA DNA-binding domain-hHSF1 chimeras bind to a LexA-binding site in a heat-regulated fashion, that single amino acid replacements disrupting the integrity of hydrophobic repeats render these chimeras constitutively trimeric and DNA binding, and that LexA itself binds stably to DNA only as a dimer but not as a monomer in our assays.

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Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

Cancers ◽

10.3390/cancers13051102 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1102

Author(s):

Alexander E. Kabakov ◽

Anna O. Yakimova

Keyword(s):

Heat Shock ◽

Tumor Cells ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Liver Tumors ◽

Oxygen Deficiency ◽

Transarterial Embolization ◽

Antiangiogenic Therapy ◽

Adaptation To Hypoxia ◽

Mesenchymal Transition

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.

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A novel homeostatic loop of sorcin drives paclitaxel-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human ovarian cancer

Oncogene ◽

10.1038/s41388-021-01891-6 ◽

2021 ◽

Author(s):

Jinguo Zhang ◽

Wencai Guan ◽

Xiaolin Xu ◽

Fanchen Wang ◽

Xin Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Calcium Binding ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Malignant Progression ◽

Bioinformatics Analyses ◽

Aberrant Expression ◽

Mesenchymal Transition ◽

E Box

AbstractThe primary chemotherapy of ovarian cancer (OC) often acquires chemoresistance. Sorcin (SRI), a soluble resistance-related calcium-binding protein, has been reported to be an oncogenic protein in cancer. However, the molecular mechanisms of SRI regulation and the role and aberrant expression of SRI in chemoresistant OC remain unclear. Here, we identified SRI as a key driver of paclitaxel (PTX)-resistance and explored its regulatory mechanism. Using transcriptome profiles, qRT-PCR, proteomics, Western blot, immunohistochemistry, and bioinformatics analyses, we found that SRI was overexpressed in PTX-resistant OC cells and the overexpression of SRI was related to the poor prognosis of patients. SRI was a key molecule required for growth, migration, and PTX-resistance in vitro and in vivo and was involved in epithelial–mesenchymal transition (EMT) and stemness. Mechanistic studies showed that miR-142-5p directly bound to the 3ʹ-UTR of SRI to suppress its expression, whereas a transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) inhibited the transcription of miR-142-5p by directly binding to the E-box fragment in the miR-142 promoter region. Furthermore, ZEB1 was negatively regulated by SRI which physically interacted with Smad4 to block its translocation from the cytosol to the nucleus. Taken together, our findings unveil a novel homeostatic loop of SRI that drives the PTX-resistance and malignant progression via Smad4/ZEB1/miR-142-5p in human OC. Targeting this SRI/Smad4/ZEB1/miR-142-5p loop may reverse the PTX-resistance.

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