Post-transcriptional regulation of cancer/testis antigen MAGEC2 expression by TRIM28 in tumor cells

Song, Xian‐Rong; Guo, Chi; Zheng, Yutian; Wang, Ying; Jin, Zhongtian; Yin, Yuqin

doi:10.1186/s12885-018-4844-1

Cited by 10 publications

(6 citation statements)

References 42 publications

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“…As a scaffolding protein that forms dimer or trimer or even higher order oligomers, TRIM28-mediated interaction with TRIM24, MDM2 and MAGE-C2 could co-exist in a large complex. As shown, introducing ectopic KRAB domains decreased TRIM28 level, which also brings down the levels of TRIM24 and, potentially, MDM2 ( Supplementary Figure S3F ) or MAGE-C2 ( 40 ). The net result is decreased ubiquitination of p53, and thus increased level of p53 protein (Figure 7C ).…”

Section: Discussionmentioning

confidence: 52%

KRAB domain of ZFP568 disrupts TRIM28-mediated abnormal interactions in cancer cells

et al. 2020

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Interactions of KRAB (Krüppel-associated box)-associated protein KAP1 [also known as TRIM28 (tripartite motif containing protein 28)] with DNA-binding KRAB zinc finger (KRAB-ZF) proteins silence many transposable elements during embryogenesis. However, in some cancers, TRIM28 is upregulated and interacts with different partners, many of which are transcription regulators such as EZH2 in MCF7 cells, to form abnormal repressive or activating complexes that lead to misregulation of genes. We ask whether a KRAB domain—the TRIM28 interaction domain present in native binding partners of TRIM28 that mediate repression of transposable elements—could be used as a tool molecule to disrupt aberrant TRIM28 complexes. Expression of KRAB domain containing fragments from a KRAB-ZF protein (ZFP568) in MCF7 cells, without the DNA-binding zinc fingers, inhibited TRIM28–EZH2 interactions and caused degradation of both TRIM28 and EZH2 proteins as well as other components of the EZH2-associated polycomb repressor 2 complex. In consequence, the product of EZH2 enzymatic activity, trimethylation of histone H3 lysine 27 level, was significantly reduced. The expression of a synthetic KRAB domain significantly inhibits the growth of breast cancer cells (MCF7) but has no effect on normal (immortalized) human mammary epithelial cells (MCF10a). Further, we found that TRIM28 is a positive regulator of TRIM24 protein levels, as observed previously in prostate cancer cells, and expression of the KRAB domain also lowered TRIM24 protein. Importantly, reduction of TRIM24 levels, by treatment with either the KRAB domain or a small-molecule degrader targeted to TRIM24, is accompanied by an elevated level of tumor suppressor p53. Taken together, this study reveals a novel mechanism for a TRIM28-associated protein stability network and establishes TRIM28 as a potential therapeutic target in cancers where TRIM28 is elevated. Finally, we discuss a potential mechanism of KRAB-ZF gene expression controlled by a regulatory feedback loop of TRIM28–KRAB.

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Section: Discussionmentioning

confidence: 52%

KRAB domain of ZFP568 disrupts TRIM28-mediated abnormal interactions in cancer cells

et al. 2020

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“…First, we found multipleMAGE family proteins (e.g. MAGEC2, MAGEB2, MAGEC1, MAGEB6) with a similar gene expression profile to those inclinical trials (MAGEA1, MAGEA4), which have been reported to be tumor specific [40][41][42] . Second, we find numerous Pregnancy-specific glycoprotein (PSG) genes which fall into the broader category of carcinoembryonic antigens (Supplementary Figure 6A).…”

Section: Bayests Accurately Estimates Tumor Specificity From Multidom...mentioning

confidence: 72%

Quantifying tumor specificity using Bayesian probabilistic modeling for drug target discovery and prioritization

Bhattacharjee

Salomonis

2023

Preprint

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In diseases such as cancer, the design of new therapeutic strategies requires extensive, costly, and unfortunately sometimes deadly testing to reveal life threatening off target effects. A crucial first step in predicting toxicity are analyses of normal RNA and protein tissue expression, which are now possible using comprehensive molecular tissue atlases. However, no standardized approaches exist for target prioritization, which instead rely on ad-hoc thresholds and manual inspection. Such issues are compounded, given that genomic and proteomic data detection sensitivity and accuracy are often problematic. Thus, quantifiable probabilistic scores for tumor specificity that address these challenges could enable the creation of new predictive models for combinatorial drug design and correlative analyses. Here, we propose a Bayesian Tumor Specificity (BayesTS) score that can naturally account for multiple independent forms of molecular evidence derving from both RNA-Seq and protein expression while preserving the uncertainty of the inference. We applied BayesTS to 24,905 human protein-coding genes across 3,644 normal samples (GTEx and TCGA) spanning 63 tissues. These analyses demonstrate the ability of BayesTS to accurately incorporate protein, RNA and tissue distribution evidence, while effectively capturing the uncertainty of these inferences. This approach prioritized well-established drug targets, while deemphasizing those which were later found to induce toxicity. BayesTS allows for the adjustment of tissue importance weights for tissues of interest, such as reproductive and physiologically dispensable tissues (e.g., tonsil, appendix), enabling clinically translatable prioritizations. Our results show that BayesTS can facilitate novel drug target discovery and can be easily generalized to unconventional molecular targets, such as splicing neoantigens. We provide the code and inferred tumor specificity predictions as a database available online (https://github.com/frankligy/BayesTS). We envision that the widespread adoption of BayesTS will facilitate improved target prioritization for oncology drug development, ultimately leading to the discovery of more effective and safer drugs.

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“…As shown in Figure 5 a, the RNA and protein levels of MAGEC2 were increased when ectopic expression of Trim28 ( Figure 5 a). The previous report demonstrated that MAGEC2 protein stability is dependent on the interaction with TRIM28 [ 40 ]. We transfected the FLAG-MAGEC2 expression vector into HEK293T and performed IP-Western blotting.…”

Section: Resultsmentioning

confidence: 99%

Generation of TRIM28 Knockout K562 Cells by CRISPR/Cas9 Genome Editing and Characterization of TRIM28-Regulated Gene Expression in Cell Proliferation and Hemoglobin Beta Subunits

Chang

Kang

Bei

et al. 2022

IJMS

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TRIM28 is a scaffold protein that interacts with DNA-binding proteins and recruits corepressor complexes to cause gene silencing. TRIM28 contributes to physiological functions such as cell growth and differentiation. In the chronic myeloid leukemia cell line K562, we edited TRIM28 using CRISPR/Cas9 technology, and the complete and partial knockout (KO) cell clones were obtained and confirmed using quantitative droplet digital PCR (ddPCR) technology. The amplicon sequencing demonstrated no off-target effects in our gene editing experiments. The TRIM28 KO cellsgrew slowly and appeared red, seeming to have a tendency towards erythroid differentiation. To understand how TRIM28 controls K562 cell proliferation and differentiation, transcriptome profiling analysis was performed in wild-type and KO cells to identify TRIM28-regulated genes. Some of the RNAs that encode the proteins regulating the cell cycle were increased (such as p21) or decreased (such as cyclin D2) in TRIM28 KO cell clones; a tumor marker, the MAGE (melanoma antigen) family, which is involved in cell proliferation was reduced. Moreover, we found that knockout of TRIM28 can induce miR-874 expression to downregulate MAGEC2 mRNA via post-transcriptional regulation. The embryonic epsilon-globin gene was significantly increased in TRIM28 KO cell clonesthrough the downregulation of transcription repressor SOX6. Taken together, we provide evidence to demonstrate the regulatory network of TRIM28-mediated cell growth and erythroid differentiation in K562 leukemia cells.

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Post-transcriptional regulation of cancer/testis antigen MAGEC2 expression by TRIM28 in tumor cells

Cited by 10 publications

References 42 publications

KRAB domain of ZFP568 disrupts TRIM28-mediated abnormal interactions in cancer cells

KRAB domain of ZFP568 disrupts TRIM28-mediated abnormal interactions in cancer cells

Quantifying tumor specificity using Bayesian probabilistic modeling for drug target discovery and prioritization

Generation of TRIM28 Knockout K562 Cells by CRISPR/Cas9 Genome Editing and Characterization of TRIM28-Regulated Gene Expression in Cell Proliferation and Hemoglobin Beta Subunits

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