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PSIP1/p75 promotes tumorigenicity in breast cancer cells by promoting the transcription of cell cycle genes

ABSTRACT: Breast cancer (BC) is a highly heterogeneous disease, both at the pathological and molecular level, and several chromatin-associated proteins play crucial roles in breast cancer initiation and progression. Here, we demonstrate the role of PSIP1 (PC4 and SF2 interacting protein)/p75 (LEDGF) in breast cancer progression. PSIP1/p75, previously identified as a chromatin-adaptor protein, is found to be upregulated in basal-like/triple negative breast cancer (TNBC) patient samples and cell lines. Immunohistochemistry in tissue arrays showed elevated levels of PSIP1 in metastatic invasive ductal carcinoma. Survival data analyses indicated that the levels of PSIP1 showed a negative association with TNBC patient survival. Depletion of PSIP1/p75 significantly reduced the tumorigenicity and metastatic properties of TNBC cell lines while its over-expression promoted tumorigenicity. Further, gene expression studies revealed that PSIP1 regulates the expression of genes controlling cell-cycle progression, cell migration, and invasion. Finally, by interacting with RNA polymerase II, PSIP1/p75 facilitates the association of RNA pol II to the promoter of cell cycle genes and thereby regulates their transcription. Our findings demonstrate an important role of PSIP1/p75 in TNBC tumorigenicity by promoting the expression of genes that control the cell cycle and tumor metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99699 | GEO | 2017/06/06

SECONDARY ACCESSION(S): PRJNA389318

REPOSITORIES: GEO

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Homo sapiens

Project description:PSIP1/p75 promotes tumorigenicity in breast cancer cells by promoting the transcription of cell cycle genes

| PRJNA389318 | ENA

Comparision of Psip1/p75 binding and Mll1 binding sites on Hox and non-Hox genes

Project description:Psip1/p75 binds to Hox genes and colocalizes with Mll1 and in Psip1 KO MEFs Mll1 occupancy is reduced over Hox genes Psip1/p75 ChIP using A300-848 abtibody (recognises p75 isoform of Psip1) and Mll1 ChIP from WT and Psip1 KO MEFs ChIP-chip

2014-06-27 | E-GEOD-49179 | biostudies-arrayexpress

Functional Characterization of lncRNA152 as an Angiogenesis-Inhibiting Tumor Suppressor in Triple-Negative Breast Cancers

Project description:Long non-coding RNAs have been implicated in many of the hallmarks of cancer. We previously annotated lncRNA152 (lnc152; a.k.a. DRAIC) and demonstrated its roles in proliferation, cell cycle progression, and regulation of the estrogen signaling pathway in breast cancer cells. Herein, we found that lnc152 is highly upregulated in luminal breast cancers, but is downregulated in triple-negative breast cancers (TNBC). Using a set of complementary experimental approaches, we found that knockdown of lnc152 promotes cell migration and invasion in luminal breast cancer cell lines. In contrast, ectopic expression of lnc152 inhibits growth, migration, invasion, and angiogenesis in TNBC cell lines. In xenograft studies in mice, lnc152 inhibited the growth and metastasis of TNBC cells. Transcriptome analysis of the xenografts indicated that lnc152 downregulates genes regulating cancer-related phenotypes, including angiogenesis. Using RNA-pull down assays coupled with LC-MS/MS analysis, we identified RBM47, a known tumor suppressor protein in breast cancer, as a lnc152-interacting protein. We found that lnc152 suppresses the aggressive phenotypes of TNBC cells by regulating the expression of RBM47. Collectively, our results demonstrate that lnc152 is an angiogenesis-inhibiting tumor suppressor that attenuates the aggressive cancer-related phenotypes found in TNBC.

2022-11-09 | GSE193634 | GEO

Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [microarray]

Project description:Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNFalpha can facilitate tumor progression and metastasis. However, our knowledge of the molecular mechanisms underlying TNBC progression mediated by inflammation is still limited. Here, we define the AP-1 transcription factor c-Jun cistrome, which is comprised of 13800 binding sites responsive to TNFalpha-induced signaling in TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFalpha-elicited transcriptome. Expression of the c-Jun-regulated pro-invasion gene program is strongly associated with clinical outcomes in TNBCs. Mechanistically, we demonstrate that c-Jun drives TNFalpha-mediated TNBC tumorigenicity by transcriptional regulation of Ninj1. As exemplified by the c-Jun bound CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-kB might be a pioneer factor and is required for the regulation of TNFalpha-inducible inflammatory genes, whereas c-Jun has little effect. Together, our results uncover AP-1 as an important determinant for inflammation-induced cancer progression, rather than inflammatory response. BT549 cells were cultured to 50% confluency and transfected with control or c-Jun siRNA for 72 hours, followed by treatment with or without TNFÎ± for 6 hours.

2016-01-20 | E-GEOD-71915 | biostudies-arrayexpress

Comparision of Psip1/p75 binding and Mll1 binding sites on Hox and non-Hox genes

Project description:Psip1/p75 binds to Hox genes and colocalizes with Mll1 and in Psip1 KO MEFs Mll1 occupancy is reduced over Hox genes

2014-06-27 | GSE49179 | GEO

Genome-wide maps of XBP1 binding sites in different breast cancer cell lines [ChIP-Seq]

Project description:We report the application of ChIP-seq, which combines chromatin immunoprecipitation (ChIP) with massively parallel DNA sequencing, to map genome-wide XBP1 binding sites in different breast cancer cell lines. We showed that HIF1M-NM-1 motif was enriched in XBP1 binding sites in triple negative breast cancer (TNBC) cell lines, but not enriched in ER positive breast cancer cell line. We also demonstrated that different breast cancer cell lines of the same sub-type had similar XBP1 binding sites, whereas different breast cancer sub-types had majorly different XBP1 binding sites. Finally, a model was applied to integrate XBP1 ChIP-seq data with expression data to predict XBP1's direct targets in TNBC cell line; the predicted direct targets were shown to be predictive of patient survival, and the prediction power was specific to TNBC patients. The above evidence indicates that XBP1 performs important functions in TNBC by interacting with HIF1M-NM-1, and such regulation mechanism is specific to TNBC, which is later proved by follow-up experiments.This study represents the first detailed anaysis of XBP1 binding sites in different breast cancer cell lines. Examination of XBP1 binding sites in 2 cell types (3 cell lines).

2013-09-26 | E-GEOD-49952 | biostudies-arrayexpress

HIV-1 integrase variants retarget viral integration and are associated with disease progression in a chronic infection cohort.

Project description:Distinct integration patterns of different retroviruses have puzzled virologists for over 20 years. The viral integrase (IN), as part of the intasome complex, docks onto the target DNA (tDNA) and catalyzes the insertion of the viral genome into the host chromatin. We identified retroviral IN amino acids directly contacting tDNA bases and affecting the local integration site sequence biases. These residues also determine the propensity of the virus to integrate into flexible tDNA sequences. Remarkably, natural polymorphisms INS119G and INR231G retarget viral integration away from gene dense regions, without affecting the interaction with the lentiviral tethering cofactor LEDGF/p75 (PSIP1). Precisely these variants were associated with rapid disease progression in a chronic HIV-1 subtype C infection cohort. These findings link integration site selection to virulence and viral evolution but also to the host immune response and antiretroviral therapy, since HIV-1 IN119 is under selection by HLA alleles and integrase inhibitors. LEDGF/p75 (PSIP1) ChIP-Seq using A300-848 antibody (recognizes p75 isoform) and input control in primary CD4+ T-cells

2015-01-26 | E-GEOD-61003 | biostudies-arrayexpress

Mitotically associated long non-coding RNA, MANCR regulates cell cycle in triple negative breast cancer cells

Project description:Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that is difficult to treat as it is unresponsive to hormone-therapy; therefore, it is imperative to identify novel, targetable regulators of progression in TNBC. Long non-coding RNAs (lncRNAs) are important regulators in breast cancer and have great potential as therapeutic targets; however, little is known about how the majority of lncRNAs function within TNBC cells. In this study, we identify a novel lncRNA, MANCR (LINC00704), which is upregulated in TNBC cells and breast cancer patient samples. Depletion of MANCR in TNBC cells results in a significant decrease in cell proliferation and viability with a concomitant increase in DNA damage. Transcriptome-wide sequencing following MANCR knockdown reveals significant differences in the expression of >2000 genes, and gene set enrichment analysis identifies changes in multiple categories related to cell cycle regulation. Furthermore, MANCR expression is highest in mitotic cells by both RT-qPCR and RNA in situ hybridization. Consistent with a possible role in cell cycle regulation, MANCR-depleted cells have a lower mitotic index and a higher incidence of defective cytokinesis. Taken together, our data reveal a role for the novel lncRNA, MANCR (mitotically-associated long non-coding RNA), in cell cycle regulation of aggressive breast cancer, and identify it as a potential therapeutic target.

2018-01-31 | GSE102155 | GEO

Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [ChIP-seq]

Project description:Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNF can facilitate tumor progression and metastasis. However, our knowledge of the molecular mechanisms underlying TNBC progression mediated by inflammation is still limited. Here, we define the AP-1 transcription factor c-Jun cistrome, which is comprised of 13800 binding sites responsive to TNFalpha-induced signaling in TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFalpha-elicited transcriptome. Expression of the c-Jun-regulated pro-invasion gene program is strongly associated with clinical outcomes in TNBCs. Mechanistically; we demonstrate that c-Jun drives TNFalpha-mediated TNBC tumorigenicity by transcriptional regulation of Ninj1. As exemplified by the c-Jun bound CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-kB might be a pioneer factor and is required for the regulation of TNFalpha-inducible inflammatory genes, whereas c-Jun has little effect. Together, our results uncover AP-1 as an important determinant for inflammation-induced cancer progression, rather than inflammatory response.

2016-01-20 | GSE71976 | GEO

Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [microarray]

2016-01-20 | GSE71915 | GEO

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