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TUSC4 functions as a tumor suppressor by regulating BRCA1’s stability via the E3 ubiquitination pathway

ABSTRACT: Expression of the tumor suppressor protein BRCA1 is frequently lost in breast cancer patients, and the loss of its expression is associated with disruption of various critical functions in cells and cancer development. In the present study, we demonstrated that microarray analysis of cells with tumor suppressor candidate 4 (TUSC4) knockdown indicated critical changes such as cell cycle, cell death pathways and a global impact to cancer development. More importantly, we observed a clear cluster pattern of TUSC4-knockdown gene profiles with established homologous recombination (HR) repair defect signature. Additionally, TUSC4 protein can physically interact with E3 ligase Herc2 and prevents BRCA1 degradation via ubiquitination pathway. Knockdown of TUSC4 expression enhanced BRCA1 polyubiquitination, leading to BRCA1 protein degradation and a marked reduction in HR repair efficiency. Notably, ectopic expression of TUSC4 effectively suppressed the proliferation, invasion, and colony formation of breast cancer cells in vitro and tumorigenesis in vivo. Furthermore, knockdown of TUSC4 expression transformed normal mammary epithelial cells and enhanced the sensitivity of U2OS cells to the treatment of poly(ADP-ribose) polymerase inhibitors. Therefore, TUSC4 may act as a bona fide tumor suppressor by regulating BRCA1 protein stability and function in breast cancer. Two groups of samples are included: 1.U2OS-shcontrol 2.U2OS-shTUSC4 knockdown. Gene expression profiles of U2OS-shTUSC4 cells were compared to that of parental U2OS-shcontrol cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Yang Peng

PROVIDER: E-GEOD-60535 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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TUSC4 functions as a tumor suppressor by regulating BRCA1’s stability via the E3 ubiquitination pathway

Project description:Expression of the tumor suppressor protein BRCA1 is frequently lost in breast cancer patients, and the loss of its expression is associated with disruption of various critical functions in cells and cancer development. In the present study, we demonstrated that microarray analysis of cells with tumor suppressor candidate 4 (TUSC4) knockdown indicated critical changes such as cell cycle, cell death pathways and a global impact to cancer development. More importantly, we observed a clear cluster pattern of TUSC4-knockdown gene profiles with established homologous recombination (HR) repair defect signature. Additionally, TUSC4 protein can physically interact with E3 ligase Herc2 and prevents BRCA1 degradation via ubiquitination pathway. Knockdown of TUSC4 expression enhanced BRCA1 polyubiquitination, leading to BRCA1 protein degradation and a marked reduction in HR repair efficiency. Notably, ectopic expression of TUSC4 effectively suppressed the proliferation, invasion, and colony formation of breast cancer cells in vitro and tumorigenesis in vivo. Furthermore, knockdown of TUSC4 expression transformed normal mammary epithelial cells and enhanced the sensitivity of U2OS cells to the treatment of poly(ADP-ribose) polymerase inhibitors. Therefore, TUSC4 may act as a bona fide tumor suppressor by regulating BRCA1 protein stability and function in breast cancer.

2014-08-21 | GSE60535 | GEO

Genome-wide analysis of BRCA1 and PALB2 [ChIP-seq and RNA-seq]

Project description:Breast and ovarian cancer susceptibility genes, BRCA1 and PALB2 have enigmatic roles in cellular growth and mammalian development. While these genes are essential for growth during early developmental programs, inactivation later in adulthood leads to increased growth and formation of tumors, leading to their designation as tumor suppressors. We performed genome-wide analysis assessing their chromatin residence and gene expression responsiveness using high throughput sequencing in breast epithelial cells. These experiments revealed a critical role for BRCA1 and PALB2 in transcriptional responsiveness to NF-kB, a crucial mediator of growth and inflammatory response during development and cancer. Importantly, we also uncovered a vital role for these proteins in response to retinoic acid (RA), a growth inhibitory signal in breast cancer cells, which may constitute the basis for their tumor suppressor activity. Comparison of the genome wide profiles of the BRCA protein complex (BRCA1 and PALB2) and phosphorylated RNAPII (P-Ser2) in MCF10A cells by ChIP-seq. Effect of BRCA1 and PALB2 knockdown (shRNAs) on transcription was assessed by RNA-seq.

2013-09-30 | E-GEOD-40591 | biostudies-arrayexpress

Genome-wide analysis of RNAs translationally regulated upon BRCA1 depletion in human mammary epithelial cells

2013-12-31 | GSE40730 | GEO

Suppression of BRCA1 sensitizes to proteasome inhibitors in DNA repair-independent manner.

Project description:Germline and somatic mutations in BRCA1predispose to breast cancer. We found that proteasome inhibitors can selectively kill BRCA1-depleted cells. The toxic response involves a deregulation of the G1/S cell cycle checkpoint via hyperphosphorylation of RB1, 53BP1-mediated arrest at G2/M checkpoint, and ERN1-mediated unfolded protein response, culminating in a TNF receptor-mediated apoptosis. The study new unexpected molecular functions for BRCA1 protein and opens a novel possibility for the treatment of BRCA1-deficient cancers. We used microarrays to detail the global programme of gene expression underlying the response of BRCA1-deficient cells to proteasome inhibitor bortezomib. We aimed to identify genes that are strongly up- or down-regulated with a combination of BRCA1 knockdown and proteasome inhibition, but none of these treatments alone before the onset of apoptosis. HeLa and U2OS cells were transfected either with a non-targeting or anti-BRCA1 siRNAs (siControl or siBRCA1, respectively), treated with bortezomib for 8 hours, after which RNA was extracted for hybridization on Affymetrix microarray. The following treatments have been performed: (T1) siControl; (T2) siControl + 20 nM bortezomib for 8h; (T3) siBRCA1; (T4) siBRCA1 + 20 nM bortezomib for 8h. All samples were used without replicas. However, all genes showing inconsistent expression pattern between the two cell lines were excluded from further consideration. Selected candidate genes were subject to validation by qRT-PCR.

2015-01-01 | E-GEOD-56280 | biostudies-arrayexpress

Genome-wide analysis of RNAs translationally regulated upon BRCA1 depletion in human mammary epithelial cells

Project description:Loss of function of the tumor suppressor BRCA1 (Breast Cancer 1) protein is responsible for numerous familial and sporadic breast cancers. We previously identified PABP1 as a novel BRCA1 partner and showed that BRCA1 modulates translation through its interaction with PABP1. We showed that the global translation was diminished in BRCA1-depleted cells and increased in BRCA1-overexpressing cells. Our findings raised the question whether BRCA1 affects translation of all cytoplasmic cellular mRNAs or whether it specifically targets a subset of mRNAs. In the present study, we investigated which mRNAs are regulated by BRCA1 using a microarray analysis of polysome-associated RNAs from BRCA1-depleted MCF7 cells, a human breast cancer cell line. We isolated mRNAs from the high-molecular-weight polysomes (fractions 12 to 18) and total cellular cytoplasmic mRNAs from the cytoplasmic fraction of MCF7 cells transiently expressing either siRNA directed against BRCA1 or control siRNA. Since we were interested in identifying the mRNAs that were translationally regulated by BRCA1, we determined the relative translatability of each mRNA. The relative translatability of an mRNA was determined by normalizing the change in abundance in polysomal mRNA to the change in abundance in total cytoplasmic mRNA for each mRNA.

2013-12-31 | E-GEOD-40730 | biostudies-arrayexpress

BRCA1 Regulates Carbohydrate Metabolism Through its RING Domain and Transcription Factor Oct1

Project description:The tumor suppressor BRCA1 regulates DNA damage responses and multiple other processes. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal RING domain. Here we show that BRCA1 promotes oxidative metabolism via degradation of Oct1, a transcription factor with pro-glycolytic/tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells towards a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype. RNAseq confirms the deregulation of metabolic genes. BRCA1 mediates direct Oct1 ubiquitylation and degradation, and mutation of two ubiquitylated Oct1 lysines insulates the protein against BRCA1-mediated destabilization. Oct1 deletion in MCF-7 breast cancer cells does not perturb growth in standard culture, but inhibits growth in soft agar and xenografts. Oct1 protein levels correlate positively with tumor aggressiveness, and inversely with BRCA1, in primary breast cancer samples. These results identify BRCA1 as an Oct1 ubiquitin ligase that catalyzes Oct1 degradation to promote oxidative metabolism.

2017-11-30 | GSE98831 | GEO

MeRIP-seq of control and TARBP2 knockdown cells

Project description:To identify changes in methylation patterns following TARBP2 knockdown, m6A-IP followed by RNA-seq was performed on breast cancer cells expressing shRNAs against TARBP2 (and non-targeting shControl cells).

2019-12-26 | GSE130893 | GEO

Changes in follistatin levels by BRCA1 may serve as a regulator of ovarian carcinogenesis

Project description:Follistatin is a folliculogenesis regulating protein that has been found in relatively high concentration in the female ovarian tissues. Follistatin acts as an antagonist to the function of Activin, which is often found elevated in ovarian carcinogenesis and thus presents a possibility for therapeutic intervention in controlling ovarian cancer. Most of the ovarian cancer occurs in its ovarian surface epithelium (OSE) cells. Although breast cancer susceptibility gene 1 (BRCA1) is a known tumor suppressor for breast cancer but its role in ovarian cancer is beginning to unfold. We have shown that in ovarian carcinoma cells (SKOV3), stable overexpression of BRCA1 stimulates Follistatin secretion and simultaneously downregulates Activin expression. Moreover, knock down of BRCA1 in immortalized OSE (IOSE) cells from human ovarian tissue demonstrates downregulation of Follistatin secretion with simultaneous up regulation of Activin expression. IOSE cells generated from an ovarian cancer patient with BRCA1 mutation failed to secrete Follistatin in the medium. Our results indicate a novel function for BRCA1 in the form of regulation of the expression of Follistatin in the ovarian cells. 3 treatments vs 3 controls

2011-07-02 | E-GEOD-30296 | biostudies-arrayexpress

The tumor suppressor BRCA1 is a translational regulator

Project description:BRCA1 inactivation is a hallmark of familial breast cancer, often encountered in aggressive triple negative breast cancers. BRCA1 is a tumor suppressor with known functions in DNA repair, transcription regulation, cell cycle control, and apoptosis. In the present study, we demonstrate that BRCA1 is also a translational regulator. Based on the combination of RNA-binding protein immunoprecipitation and microarray analysis, as well as polysome profiling, we identified a subset of mRNAs translationally regulated by BRCA1 and coding for proteins whose functions play major role in cancer. We found that the level of these key proteins is similarly controlled in human mammary tumors according to their BRCA1-status. Therefore, our results propose translational control as a novel molecular mechanism with clinical relevance through which BRCA1 is a tumor suppressor.

2020-05-21 | GSE119886 | GEO

Expression data of CHK1 shRNA knockdown and control shRNA in U2OS cells

Project description:Homologous recombination-mediated DNA repair deficiency (HRD) predisposes to cancer development, but also provides therapeutic opportunities. Here, we identified an HRD gene signature that robustly predicted HRD status. Unexpectedly, concurrent loss of PTEN in BRCA1-deficient cells might extensively rewire the HR repair network and confer resistance to PARP inhibitor, partially through over-expression of TTK. We used the HRD gene signature as a drug discovery tool and found several PARP-inhibitor-synergizing agents through the connectivity map. Thus gene expression profiling can be used to define the functional status of the HR repair network providing prognostic and therapeutic information. Various shRNAs that target genes involved in homologous recombination (HR) were transfected in MCF-10A non-transformed breast cells lines. Stable HR gene knockdown MCF-10A cells were seeded 200000 at 10 cm plate. Cells were harvested after 48 hours culturing and used for gene expression profiling. The shRNA that target CHK1 gene was transfected in human osteosarcoma U2OS cell line by lentiviral particles and selected stable CHK1 knockdown U2OS cells. Scrambled control shRNA-transfected U2OS cells were applying as control. Both stable CHK1 knockdown and control U2OS cells were seeded with 2 x 10^5 cells at 10 cm culture plate. Cells were cultured in McCOY 5A medium with 10% FBS and harvested after 48 hours culturing. mRNA was extracted from collected cells and performing gene expression profiling. Three biological replicates were applied.

2014-01-24 | E-GEOD-54267 | biostudies-arrayexpress

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