Enhanced MYC association with the NuA4 histone acetyltransferase complex mediated by the adenovirus E1A N-terminal domain activates a subset of MYC target genes highly expressed in cancer cells

The SAGA complex contains two enzymatic modules, which house histone acetyltransferase (HAT) and deubiquitinase (DUB) activities. USP22 is the catalytic subunit of the DUB module, but two adaptor proteins, ATXN7L3 and ENY2, are necessary for DUB activity toward histone H2Bub1 and other substrates. ATXN7L3B shares 74% identity with the N-terminal region of ATXN7L3, but the functions of ATXN7L3B are not known. Here we report that ATXN7L3B interacts with ENY2 but not other SAGA components. Even though ATXN7L3B localizes in the cytoplasm, ATXN7L3B overexpression increases H2Bub1 levels, while overexpression of ATXN7L3 decreases H2Bub1 levels. In vitro , ATXN7L3B competes with ATXN7L3 to bind ENY2, and in vivo , knockdown of ATXN7L3B leads to concomitant loss of ENY2. Unlike the ATXN7L3 DUB complex, a USP22-ATXN7L3B-ENY2 complex cannot deubiquitinate H2Bub1 efficiently in vitro . Moreover, ATXN7L3B knockdown inhibits migration of breast cancer cells in vitro and limits expression of ER target genes. Collectively, our studies suggest that ATXN7L3B regulates H2Bub1 levels and SAGA DUB activity through competition for ENY2 binding.

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Androgen receptor: acting in the three-dimensional chromatin landscape of prostate cancer cells

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci.2010.055 ◽

2011 ◽

Vol 5 (1) ◽

Author(s):

Harri Makkonen ◽

Jorma J. Palvimo

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Binding Sites ◽

Target Genes ◽

Three Dimensional ◽

Regulatory Elements ◽

Gene Promoters ◽

Loop Formation ◽

Prostate Cancer Cells

AbstractAndrogen receptor (AR) acts as a hormone-controlled transcription factor that conveys the messages of both natural and synthetic androgens to the level of genes and gene programs. Defective AR signaling leads to a wide array of androgen insensitivity disorders, and deregulated AR function, in particular overexpression of AR, is involved in the growth and progression of prostate cancer. Classic models of AR action view AR-binding sites as upstream regulatory elements in gene promoters or their proximity. However, recent wider genomic screens indicate that AR target genes are commonly activated through very distal chromatin-binding sites. This highlights the importance of long-range chromatin regulation of transcription by the AR, shifting the focus from the linear gene models to three-dimensional models of AR target genes and gene programs. The capability of AR to regulate promoters from long distances in the chromatin is particularly important when evaluating the role of AR in the regulation of genes in malignant prostate cells that frequently show striking genomic aberrations, especially gene fusions. Therefore, in addition to the mechanisms of DNA loop formation between the enhancer bound ARs and the transcription apparatus at the target core promoter, the mechanisms insulating distally bound ARs from promiscuously making contacts and activating other than their normal target gene promoters are critical for proper physiological regulation and thus currently under intense investigation. This review discusses the current knowledge about the AR action in the context of gene aberrations and the three-dimensional chromatin landscape of prostate cancer cells.

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Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns

Carcinogenesis ◽

10.1093/carcin/bgs331 ◽

2012 ◽

Vol 34 (2) ◽

pp. 248-256 ◽

Cited By ~ 30

Author(s):

C. L. Doig ◽

P. K. Singh ◽

V. K. Dhiman ◽

J. L. Thorne ◽

S. Battaglia ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Methylation ◽

Cancer Cells ◽

Target Genes ◽

Prostate Cancer Cells ◽

Methylation Patterns

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Synthesizing artificial devices that redirect cellular information at will

eLife ◽

10.7554/elife.31936 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 5

Author(s):

Yuchen Liu ◽

Jianfa Li ◽

Zhicong Chen ◽

Weiren Huang ◽

Zhiming Cai

Keyword(s):

Cancer Cells ◽

Signaling Pathway ◽

Gene Networks ◽

Target Genes ◽

Logic Gates ◽

Feedback Loops ◽

Oncogenic Signaling ◽

Multiple Signals ◽

Translational Level ◽

At Will

Natural signaling circuits could be rewired to reprogram cells with pre-determined procedures. However, it is difficult to link cellular signals at will. Here, we describe signal-connectors—a series of RNA devices—that connect one signal to another signal at the translational level. We use them to either repress or enhance the translation of target genes in response to signals. Application of these devices allows us to construct various logic gates and to incorporate feedback loops into gene networks. They have also been used to rewire a native signaling pathway and even to create novel pathways. Furthermore, logical AND gates based on these devices and integration of multiple signals have been used successfully for identification and redirection of the state of cancer cells. Eventually, the malignant phenotypes of cancers have been reversed by rewiring the oncogenic signaling from promoting to suppressing tumorigenesis. We provide a novel platform for redirecting cellular information.

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Dpp signaling thresholds in the dorsal ectoderm of the Drosophila embryo

Development ◽

10.1242/dev.127.15.3305 ◽

2000 ◽

Vol 127 (15) ◽

pp. 3305-3312 ◽

Cited By ~ 5

Author(s):

H.L. Ashe ◽

M. Mannervik ◽

M. Levine

Keyword(s):

Gene Expression ◽

Target Genes ◽

Histone Acetyltransferase ◽

Cell Types ◽

Drosophila Embryo ◽

Present Evidence ◽

Drosophila Homolog ◽

Dorsal Ectoderm ◽

Transgenic Embryos ◽

Different Cell Types

The dorsal ectoderm of the Drosophila embryo is subdivided into different cell types by an activity gradient of two TGF(β) signaling molecules, Decapentaplegic (Dpp) and Screw (Scw). Patterning responses to this gradient depend on a secreted inhibitor, Short gastrulation (Sog) and a newly identified transcriptional repressor, Brinker (Brk), which are expressed in neurogenic regions that abut the dorsal ectoderm. Here we examine the expression of a number of Dpp target genes in transgenic embryos that contain ectopic stripes of Dpp, Sog and Brk expression. These studies suggest that the Dpp/Scw activity gradient directly specifies at least three distinct thresholds of gene expression in the dorsal ectoderm of gastrulating embryos. Brk was found to repress two target genes, tailup and pannier, that exhibit different limits of expression within the dorsal ectoderm. These results suggest that the Sog inhibitor and Brk repressor work in concert to establish sharp dorsolateral limits of gene expression. We also present evidence that the activation of Dpp/Scw target genes depends on the Drosophila homolog of the CBP histone acetyltransferase.

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Identification of target genes in breast cancer cells directly regulated by the SRC-3/AIB1 coactivator

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0409578102 ◽

2005 ◽

Vol 102 (5) ◽

pp. 1339-1344 ◽

Cited By ~ 66

Author(s):

P. Labhart ◽

S. Karmakar ◽

E. M. Salicru ◽

B. S. Egan ◽

V. Alexiadis ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Target Genes

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Tumor-suppressor function of Beclin 1 in breast cancer cells requires E-cadherin

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2020478118 ◽

2021 ◽

Vol 118 (5) ◽

pp. e2020478118

Author(s):

Tobias Wijshake ◽

Zhongju Zou ◽

Beibei Chen ◽

Lin Zhong ◽

Guanghua Xiao ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Target Genes ◽

Cellular Proliferation ◽

Beclin 1 ◽

Beta Catenin ◽

A Genome ◽

E Cadherin

Beclin 1, an autophagy and haploinsufficient tumor-suppressor protein, is frequently monoallelically deleted in breast and ovarian cancers. However, the precise mechanisms by which Beclin 1 inhibits tumor growth remain largely unknown. To address this question, we performed a genome-wide CRISPR/Cas9 screen in MCF7 breast cancer cells to identify genes whose loss of function reverse Beclin 1-dependent inhibition of cellular proliferation. Small guide RNAs targeting CDH1 and CTNNA1, tumor-suppressor genes that encode cadherin/catenin complex members E-cadherin and alpha-catenin, respectively, were highly enriched in the screen. CRISPR/Cas9-mediated knockout of CDH1 or CTNNA1 reversed Beclin 1-dependent suppression of breast cancer cell proliferation and anchorage-independent growth. Moreover, deletion of CDH1 or CTNNA1 inhibited the tumor-suppressor effects of Beclin 1 in breast cancer xenografts. Enforced Beclin 1 expression in MCF7 cells and tumor xenografts increased cell surface localization of E-cadherin and decreased expression of mesenchymal markers and beta-catenin/Wnt target genes. Furthermore, CRISPR/Cas9-mediated knockout of BECN1 and the autophagy class III phosphatidylinositol kinase complex 2 (PI3KC3-C2) gene, UVRAG, but not PI3KC3-C1–specific ATG14 or other autophagy genes ATG13, ATG5, or ATG7, resulted in decreased E-cadherin plasma membrane and increased cytoplasmic E-cadherin localization. Taken together, these data reveal previously unrecognized cooperation between Beclin 1 and E-cadherin–mediated tumor suppression in breast cancer cells.

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