Level of FACT defines the transcriptional landscape and aggressive phenotype of breast cancer cells

Fleyshman, Daria; Prendergast, Laura; Safina, Alfiya; Paszkiewicz, Geraldine; Commane, Mairead; Morgan, Kelsey T.; Attwood, Kristopher; Gurova, Katerina V.

doi:10.18632/oncotarget.15656

Cited by 45 publications

(59 citation statements)

References 53 publications

(89 reference statements)

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“…This cannot be explained based on nonrepresentative population, since established predictive markers (stage, grade, hormone receptor, and Her2 status) demonstrated expected correlations (Figures S4 and S5). Functional studies with BrCa cells differing in the basal level of FACT or upon genetic knockdown of FACT11 are in line with the correlation of high SSRP1 and the presence of established markers of poor prognosis. Weak correlation with overall survival may suggest that input of FACT into aggressive behavior of all types of BrCa is weak but may become more significant within specific subgroups.…”

Section: Discussionsupporting

confidence: 60%

“…Of great importance, it was also observed that FACT, at the protein level, is expressed to varying degrees in many breast tumors but not in normal breast tissues 10. Upon comparison of BrCa cells of the same subtype, we saw that cells with high levels of FACT were more aggressive than those with low levels of FACT, and upon equalization of FACT levels via short hairpin RNA, the cells with high levels of FACT were converted to a less aggressive phenotype 11. In the same cohort of BrCa patients described earlier, we observed a greater correlation of SSRP1 level with grade than with the stage of the disease and a strong correlation of SSRP1 status between matched primary and metastatic lesions 1.…”

Section: Introductionmentioning

confidence: 91%

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Prognostic value of histone chaperone FACT subunits expression in breast cancer

Attwood¹,

Fleyshman²,

Prendergast³

et al. 2017

BCTT

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Understanding the underlying reasons for tumor aggressiveness, such as why some tumors grow slowly and locally, while others rapidly progress to a lethal metastatic disease, is still limited. This is especially critical in breast cancer (BrCa) due to its high prevalence and also due to the possibility that it can be detected early. Several oncogenes and tumor suppressors have been identified and are used in the prognosis and treatment of BrCa. However, even with these markers, the outcome within BrCa subtypes is highly variable. Chromatin organization has long been acknowledged as a factor that plays an important role in tumor progression, but molecular mechanisms defining chromatin dynamics are largely missing. We have recently found that histone chaperone FACT (facilitates chromatin transcription) is overexpressed in ~18–20% of BrCa cases. FACT is elevated upon transformation of mammary epithelial cells and is essential for viability of tumor cells. BrCa cells with high FACT have a more aggressive transcriptional program than those with low FACT cells. Based on this we propose that FACT may be a marker of aggressive BrCa. In this study, we aimed to comprehensively characterize the pattern of FACT expression in BrCa in relation to other molecular and clinical prognostic markers. We developed and tested an assay for the detection and quantitation of protein levels of both FACT subunits, SSRP1, and SPT16, in clinical samples. We compared the value of mRNA and protein as potential markers of disease aggressiveness using a large cohort of patients (n=1092). We demonstrated that only SSRP1 immunohistochemical staining is a reliable indicator of FACT levels in tumor samples. High SSRP1 correlated with known markers of poor prognosis, such as negative hormone receptor status, presence of Her2, high-grade tumors, and tumors of later clinical stage. At the same time, no strong correlation between SSRP1 expression and survival was detected when all samples were analyzed together. Clear trend toward longer survival of patients with low or no SSRP1 expression in tumor samples was seen in several subgroups of patients, and most importantly significant association of high SSRP1 expression with shorter disease-free survival was detected in patients with early-stage and low-grade BrCa, the category of patients with the highest demand in predictive marker of disease progression.

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Section: Discussionsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 91%

Prognostic value of histone chaperone FACT subunits expression in breast cancer

Attwood¹,

Fleyshman²,

Prendergast³

et al. 2017

BCTT

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“…13,21,22 FACT is involved in chromatin remodeling during transcription, replication and DNA damage repair and has been shown to drive in vitro cell transformation. 15,23,24 C-trapping induced by CBL0137 exhausts cellular FACT, thereby preventing the protein from exerting its normal functions in transcription, replication and DNA damage repair in cancer cells. 15,23,24 C-trapping induced by CBL0137 exhausts cellular FACT, thereby preventing the protein from exerting its normal functions in transcription, replication and DNA damage repair in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…23 In addition, FACT is overexpressed in multiple types of tumors and expression of this complex is strongly associated with poorly differentiated, aggressive cancers with low overall survival, making it an attractive anticancer target. 15,23,24 C-trapping induced by CBL0137 exhausts cellular FACT, thereby preventing the protein from exerting its normal functions in transcription, replication and DNA damage repair in cancer cells. 13,14 Based on this action, CBL0137 has been shown to be highly effective in potentiating established DNA damage-inducing chemotherapies in solid cancer models by inhibiting FACT-mediated DNA repair.…”

Section: Introductionmentioning

confidence: 99%

Potent antileukemic activity of curaxin CBL0137 against MLL‐rearranged leukemia

Somers

Kosciolek

Bongers

et al. 2019

Intl Journal of Cancer

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Around 10% of acute leukemias harbor a rearrangement of the MLL/KMT2A gene, and the presence of this translocation results in a highly aggressive, therapy‐resistant leukemia subtype with survival rates below 50%. There is a high unmet need to identify safer and more potent therapies for MLL‐rearranged (MLL‐r) leukemia that can be combined with established chemotherapeutics to decrease treatment‐related toxicities. The curaxin, CBL0137, has demonstrated nongenotoxic anticancer and chemopotentiating effects in a number of preclinical cancer models and is currently in adult Phase I clinical trials for solid tumors and hematological malignancies. The aim of our study was to investigate whether CBL0137 has potential as a therapeutic and chemopotentiating compound in MLL‐r leukemia through a comprehensive analysis of its efficacy in preclinical models of the disease. CBL0137 decreased the viability of a panel of MLL‐r leukemia cell lines (n = 12) and xenograft cells derived from patients with MLL‐r acute lymphoblastic leukemia (ALL, n = 3) in vitro with submicromolar IC50s. The small molecule drug was well‐tolerated in vivo and significantly reduced leukemia burden in a subcutaneous MV4;11 MLL‐r acute myeloid leukemia model and in patient‐derived xenograft models of MLL‐r ALL (n = 5). The in vivo efficacy of standard of care drugs used in remission induction for pediatric ALL was also potentiated by CBL0137. CBL0137 exerted its anticancer effect by trapping Facilitator of Chromatin Transcription (FACT) into chromatin, activating the p53 pathway and inducing an Interferon response. Our findings support further preclinical evaluation of CBL0137 as a new approach for the treatment of MLL‐r leukemia.

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“…breast cancer13,31 and hepatic carcinoma (HCC) 23. Significantly shortened survival is observed in patients with high SSRP1 expression compared with patients with low SSRP1 expression.…”

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confidence: 99%

SSRP1 promotes colorectal cancer progression and is negatively regulated by miR‐28‐5p

Guo

et al. 2019

J Cellular Molecular Medi

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In this study, microarray data analysis, real‐time quantitative PCR and immunohistochemistry were used to detect the expression levels of SSRP1 in colorectal cancer (CRC) tissue and in corresponding normal tissue. The association between structure‐specific recognition protein 1 (SSRP1) expression and patient prognosis was examined by Kaplan‐Meier analysis. SSRP1 was knocked down and overexpressed in CRC cell lines, and its effects on proliferation, cell cycling, migration, invasion, cellular energy metabolism, apoptosis, chemotherapeutic drug sensitivity and cell phenotype‐related molecules were assessed. The growth of xenograft tumours in nude mice was also assessed. MiRNAs that potentially targeted SSRP1 were determined by bioinformatic analysis, Western blotting and luciferase reporter assays. We showed that SSRP1 mRNA levels were significantly increased in CRC tissue. We also confirmed that this upregulation was related to the terminal tumour stage in CRC patients, and high expression levels of SSRP1 predicted shorter disease‐free survival and faster relapse. We also found that SSRP1 modulated proliferation, metastasis, cellular energy metabolism and the epithelial‐mesenchymal transition in CRC. Furthermore, SSRP1 induced apoptosis and SSRP1 knockdown augmented the sensitivity of CRC cells to 5‐fluorouracil and cisplatin. Moreover, we explored the molecular mechanisms accounting for the dysregulation of SSRP1 in CRC and identified microRNA‐28‐5p (miR‐28‐5p) as a direct upstream regulator of SSRP1. We concluded that SSRP1 promotes CRC progression and is negatively regulated by miR‐28‐5p.

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Level of FACT defines the transcriptional landscape and aggressive phenotype of breast cancer cells

Cited by 45 publications

References 53 publications

Prognostic value of histone chaperone FACT subunits expression in breast cancer

Prognostic value of histone chaperone FACT subunits expression in breast cancer

Potent antileukemic activity of curaxin CBL0137 against MLL‐rearranged leukemia

SSRP1 promotes colorectal cancer progression and is negatively regulated by miR‐28‐5p

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