Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Sunde, Jan; Donninger, Howard; Wu, Kongming; Johnson, Michael E.; Pestell, Richard G.; Rose, G. Scott; Mok, Samuel C.; Brady, John; Bonome, Tomás; Birrer, Michael J.

doi:10.1158/0008-5472.can-06-0683

Cited by 89 publications

(89 citation statements)

References 41 publications

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“…We recently showed that overexpression of Bcl-2 and like inhibitors in tumor cells can potentially be overcome by combining hGrzB and a BH3-mimetic agent such as ABT-737 and that the hGrzB death signal is remarkably long lived. 39 The well-described capacity of various human cancers to downregulate PCAF or ADA3 levels [40][41][42][43] would be expected to blunt combination therapies such as this, by repressing the latent pro-apoptotic signal provided by tBid.…”

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confidence: 99%

“…53 Finally, downregulation of PCAF has been observed in esophageal squamous cell carcinoma, ovarian and colorectal cancer. [40][41][42] Exactly how reduced expression and/or function of PCAF and ADA3 might lead to human diseases including cancer remains unclear. Small molecule inhibitors of PCAF have been reported; however, further studies on their specificity and role in disease are warranted 52,54 as is a further exploration of the potential impact of PCAF/ADA3 on immune-based cancer therapies.…”

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A functional genomics screen identifies PCAF and ADA3 as regulators of human granzyme B-mediated apoptosis and Bid cleavage

et al. 2014

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The human lymphocyte toxins granzyme B (hGrzB) and perforin cooperatively induce apoptosis of virus-infected or transformed cells: perforin pores enable entry of the serine protease hGrzB into the cytosol, where it processes Bid to selectively activate the intrinsic apoptosis pathway. Truncated Bid (tBid) induces Bax/Bak-dependent mitochondrial outer membrane permeability and the release of cytochrome c and Smac/Diablo. To identify cellular proteins that regulate perforin/hGrzB-mediated Bid cleavage and subsequent apoptosis, we performed a gene-knockdown (KD) screen using a lentiviral pool of short hairpin RNAs embedded within a miR30 backbone (shRNAmiR). We transduced HeLa cells with a lentiviral pool expressing shRNAmiRs that target 1213 genes known to be involved in cell death signaling and selected cells with acquired resistance to perforin/hGrzB-mediated apoptosis. Twenty-two shRNAmiRs were identified in the positive-selection screen including two, PCAF and ADA3, whose gene products are known to reside in the same epigenetic regulatory complexes. Small interfering (si)RNA-mediated gene-KD of PCAF or ADA3 also conferred resistance to perforin/hGrzB-mediated apoptosis providing independent validation of the screen results. Mechanistically, PCAF and ADA3 exerted their pro-apoptotic effect upstream of mitochondrial membrane permeabilization, as indicated by reduced cytochrome c release in PCAF-KD cells exposed to perforin/hGrzB. While overall levels of Bid were unaltered, perforin/hGrzB-mediated cleavage of Bid was reduced in PCAF-KD or ADA3-KD cells. We discovered that PCAF-KD or ADA3-KD resulted in reduced expression of PACS2, a protein implicated in Bid trafficking to mitochondria and importantly, targeted PACS2-KD phenocopied the effect of PCAF-KD or ADA3-KD. We conclude that PCAF and ADA3 regulate Bid processing via PACS2, to modulate the mitochondrial cell death pathway in response to hGrzB.

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A functional genomics screen identifies PCAF and ADA3 as regulators of human granzyme B-mediated apoptosis and Bid cleavage

et al. 2014

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“…Vertebrate homologs of ey (Pax6), so (Six), eya (Eya), and dac (DACH1) have been identified, and the human DACH1 (Dach1 in mice) gene encodes a protein composed of two highly conserved domains, dachshund domain 1 (DD1, also known as Box-N) with a predicted helix-turn-helix structure, and dachshund domain 2 (DD2, also known as Box-C). Altered expression of DACH1 has been reported in a variety of human tumors (5)(6)(7)(8)(9). DACH1 is expressed widely in normal epithelial tissues, and reduced DACH1 expression predicts poor outcome of breast and endometrial cancer patients (6,9).…”

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Transcription Elongation Regulator 1 Is a Co-integrator of the Cell Fate Determination Factor Dachshund Homolog 1

Zhou

Liu

Zhang

et al. 2010

Journal of Biological Chemistry

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Development of the compound eye in Drosophila is tightly regulated by the retinal determination gene network (RDGN), 3 which includes a number of proteins encoded by genes such as twin of eyeless (toy), eyeless (ey), sine oculis (so), and eyes absent (eya) (1). The Dachshund (dac) gene was originally cloned as a dominant inhibitor of ellipse. Genetic deletion of dac causes eye-and wing-specific defects in Drosophila (2). Ectopic expression of the dac gene, alone or together with so and eya, results in ectopic eye formation (3, 4). Vertebrate homologs of ey (Pax6), so (Six), eya (Eya), and dac (DACH1) have been identified, and the human DACH1 (Dach1 in mice) gene encodes a protein composed of two highly conserved domains, dachshund domain 1 (DD1, also known as Box-N) with a predicted helix-turn-helix structure, and dachshund domain 2 (DD2, also known as Box-C). Altered expression of DACH1 has been reported in a variety of human tumors (5-9). DACH1 is expressed widely in normal epithelial tissues, and reduced DACH1 expression predicts poor outcome of breast and endometrial cancer patients (6, 9). DACH1 represses TGF-␤ signaling, reduces DNA synthesis, and reverts the tumorigenic phenotypes induced by the oncogenes such as ErbB2, Ras, Src, and Myc in human mammary cell lines (10, 11). Reintroduction of DACH1 into breast cancer cells inhibits cellular proliferation and migration/invasion in vitro and tumor initiation and metastasis in vivo (6, 11). Crystallization of the human DACH1 Box-N revealed that DACH1 protein forms an ␣/␤ structure resembling a DNA binding motif found in the winged helix/forkhead subgroup of transcriptional factors (12). DACH1 is capable of binding both naked DNA and the chromatin DNA template through its Box-N domain, and the DNA binding is independent of protein association with other DACH1-binding partners (13). A subsequent study using cyclic amplification and selection of targets (CAST) identified a DNA sequence that is specific for DACH1 binding (14). The DACH1 DNA binding sequence resembles a Forkhead protein binding site, and DACH1 competes with FOXM1 from being recruited to the promoter of FOXM1 target genes. The Forkhead Box (FOX) proteins are a family of evolutionarily conserved transcriptional regulators involved in diverse biological processes (15). Deregulation of FOX protein function in human tumorigenesis may occur by alteration in upstream regulators or genetic events such as * This work was supported, in whole or in part, by National Institutes of Health Grants R01CA70896, R01CA75503, and R01CA86072 (to R. G. P.

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“…Suppressed and lost expressions of Smad4 are associated with the increase of tumorigenicity for nude mice colon carcinoma cells (9), enhancement of liver metastasis in colorectal cancer patients (10), promotion of tumor-promoting pathway in pancreatic cancer (11) and tumor metastasis capacity increase for NSCL cell (12). Down-regulation of Smad4 was discovered in advanced-stage ovarian cancers patients, which implicates that Smad4 might function through TGF-β signaling pathway (13).…”

Section: Discussionmentioning

confidence: 99%

“…For non-small-cell lung carcinoma cells, Smad4 could prevent their metastasis by inhibiting tumor angiogenesis by decreasing VEGF and increasing TSP1 expressions at both protein and mRNA levels (12). Down-regulated Smad4 was observed in microdissected specimens from patients suffering with advanced-stage ovarian cancers, which suggested that Smad4 might enhance TGF-β signaling (13). However, is Smad4 really associated with the tumor invasion and metastasis of ovarian cancer?…”

Section: Introductionmentioning

confidence: 99%

Smad4 mediates malignant behaviors of human ovarian carcinoma cell through the effect on expressions of E-cadherin, plasminogen activator inhibitor-1 and VEGF

Chen¹,

Sun²,

Liu³

et al. 2010

BMB Reports

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Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Cited by 89 publications

References 41 publications

A functional genomics screen identifies PCAF and ADA3 as regulators of human granzyme B-mediated apoptosis and Bid cleavage

A functional genomics screen identifies PCAF and ADA3 as regulators of human granzyme B-mediated apoptosis and Bid cleavage

Transcription Elongation Regulator 1 Is a Co-integrator of the Cell Fate Determination Factor Dachshund Homolog 1

Smad4 mediates malignant behaviors of human ovarian carcinoma cell through the effect on expressions of E-cadherin, plasminogen activator inhibitor-1 and VEGF

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