Identification of PBX1 Target Genes in Cancer Cells by Global Mapping of PBX1 Binding Sites

Thiaville, Michelle M.; Stoeck, Alexander; Chen, Li; Wu, Ren‐Chin; Magnani, Luca; Oidtman, Jessica; Shih, Ie Ming; Lupien, Mathieu; Wang, Tian Li

doi:10.1371/journal.pone.0036054

Cited by 41 publications

(55 citation statements)

References 28 publications

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“…Chromatin immunoprecipitation (ChIP) was performed as previously described (8). EMSA was performed using the methods previously described by us (9)(10)(11).…”

Section: Chromatin Immunoprecipitation and Electrophoretic Mobility Smentioning

confidence: 99%

“…We previously identified the PBX1-regulated transcriptome by comparing shRNA-mediated PBX1 silencing in OVCAR3 ovarian cancer cells with the control cells without gene silencing (8). To determine whether PBX1 over-expression in recurrent tumors correlated with clinical outcome, we measured the PBX1 mRNA levels in effusion samples from women with ovarian HGSC.…”

Section: Comparison Of Pbx1-regulated and Stem Cell Transcriptomesmentioning

confidence: 99%

“…Using the genome-wide NimbleGen ChIP-on-chip arrays, we previously reported direct target genes of PBX1 in OVCAR3 cells (8). The high confidence promoter occupancy list (with FDR <0.05) included a total of 1,079 genes whose promoters showed significant PBX1 binding peaks (Supplementary Table S1 Table S2).…”

Section: Pbx1 Regulates Genes Involved In Stemness Tissue Injury Resmentioning

confidence: 99%

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Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1

et al. 2016

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The evolution of chemoresistance is a fundamental characteristic of cancer that ultimately defeats its clinical management. However, it may be possible improve patient outcomes significantly by defeating nodal resistance mechanisms which cancers rely upon during the evolution to an untreatable state.Here we report an essential role for upregulation of the stem cell reprogramming factor PBX1 in mediating chemoresistance in recurrent ovarian carcinomas. In clinical specimens, high levels of PBX1 expression correlated with shorter survival in post-chemotherapy ovarian cancer patients. In tumor cells with low endogenous expression of PBX1, its enforced expression promoted cancer stem cell-like phenotypes, including most notably an increase in resistance to platinum-based therapy used most commonly for management of this disease. Conversely, silencing PBX1 in platinum-resistant cells that overexpressed PBX1 sensitized them to platinum treatment and reduced their stem-likeproperties. An analysis of published genome-wide chromatin immunoprecipitation data indicated that PBX1 binds directly to promoters of genes involved in stem cell maintenance and the response to tissue injury. We confirmed direct regulation of one of these genes, STAT3, demonstrating that the PBX1 binding motif at its promoter acted to positively regulate STAT3 transcription. Pursing this connection, we determined that a STAT3/JAK2 inhibitor could potently sensitize platinum-resistant cells to carboplatin and suppress their growth in vivo. Our findings offer a mechanistic rationale to target the PBX1/STAT3 axis to defeat a key mechanism of chemoresistance in ovarian cancers and possibly other human cancers.3

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“…Chromatin immunoprecipitation (ChIP) was performed as previously described (8). EMSA was performed using the methods previously described by us (9)(10)(11).…”

Section: Chromatin Immunoprecipitation and Electrophoretic Mobility Smentioning

confidence: 99%

Section: Comparison Of Pbx1-regulated and Stem Cell Transcriptomesmentioning

confidence: 99%

Section: Pbx1 Regulates Genes Involved In Stemness Tissue Injury Resmentioning

confidence: 99%

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Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1

et al. 2016

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“…CUX2 binding in mouse liver chromatin is described by a motif (9) most similar to the motifs for HNF6 (31), CUX1/CDP (32), and another homeodomain protein, PBX1 (33). These three factors and several other homeodomain-containing proteins are regulated by CUX2, as indicated by their responsiveness to CUX2 knockdown in female liver and/or CUX2 overexpression in male liver (9), suggesting a complex interplay between CUX2 and other homeodomain transcription factors.…”

mentioning

confidence: 93%

Cross Talk Between GH-Regulated Transcription Factors HNF6 and CUX2 in Adult Mouse Liver

Conforto

Steinhardt

Waxman

2015

Molecular Endocrinology

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Hepatocyte-enriched nuclear factor (HNF)6 and CUX2 are GH and STAT5-regulated homeobox transcription factors. CUX2 shows female-specific expression and contributes to liver sex differences by repressing many male-biased genes and inducing many female-biased genes, whereas HNF6 is expressed at similar levels in male and female liver. In cell-based transfection studies, CUX2 inhibited HNF6 transcriptional regulation of the sex-specific gene promoters CYP2C11 and CYP2C12, blocking HNF6 repression of CYP2C11 and HNF6 activation of CYP2C12. These inhibitory actions of CUX2 can be explained by competition for HNF6 DNA binding, as demonstrated by in vitro EMSA analysis and validated in vivo by global analysis of the HNF6 cistrome. Approximately 40 000 HNF6-binding sites were identified in mouse liver chromatin, including several thousand sites showing significant sex differences in HNF6 binding. These sex-biased HNF6-binding sites showed strong enrichment for correspondingly sex-biased DNase hypersensitive sites and for proximity to genes showing local sex-biased chromatin marks and a corresponding sex-biased expression. Further, approximately 90% of the genome-wide binding sites for CUX2 were also bound by HNF6. These HNF6/CUX2 common binding sites were enriched for genomic regions more accessible in male than in female mouse liver chromatin and showed strongest enrichment for male-biased genes, suggesting CUX2 displacement of HNF6 as a mechanism to explain the observed CUX2 repression of male-biased genes in female liver. HNF6 binding was sex independent at a majority of its binding sites, and HNF6 peaks were frequently associated with cobinding by multiple other liver transcription factors, consistent with HNF6 playing a global regulatory role in both male and female liver.

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“…2D), raising the possibility that additional cofactors might be required for the stabilization of the Meis-Pbx1 complex, as already shown in other contexts (37,38,39). Alternatively, other TALE family members may be more suitable cofactors in this context.…”

Section: Dose-response Luc Assays Confirmed Several Trs Candidates Asmentioning

confidence: 78%

A trans-Regulatory Code for the Forebrain Expression of Six3.2 in the Medaka Fish

Beccari

Marco-Ferreres

Tabanera

et al. 2015

Journal of Biological Chemistry

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Background:The transcription factor Six3 is key element of forebrain specification, but its upstream regulators are unknown. Results: A systematic search in medaka fish identifies and functionally characterizes novel Six3 regulators. Conclusion:The spatio-temporal regulation of Six3 depends on a few trans-acting factors. Significance: This study provides new information on how forebrain neuronal diversity is originated.

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Identification of PBX1 Target Genes in Cancer Cells by Global Mapping of PBX1 Binding Sites

Cited by 41 publications

References 28 publications

Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1

Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1

Cross Talk Between GH-Regulated Transcription Factors HNF6 and CUX2 in Adult Mouse Liver

A trans-Regulatory Code for the Forebrain Expression of Six3.2 in the Medaka Fish

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