CPSF6 is a Clinically Relevant Breast Cancer Vulnerability Target

Binothman, Najat; Hachim, Ibrahim Y.; Lebrun, Jean-Jacques; Ali, Suhad

doi:10.1016/j.ebiom.2017.06.023

Cited by 45 publications

(39 citation statements)

References 38 publications

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“…The ADAR-interacting proteins we identified included DHX15, RPS14, and ELAVL1, which were previously reported to regulate editing at specific sites, and SFPQ, HNRNPH1 and PTBP1, which are known post-transcriptional regulators of ADARs (Hirose et al, 2014; Yang et al, 2015). We also identified known ADAR-interacting protein CPSF6 and proteins involved in L1 Line element retrotransposition that were previously found in a complex with ADAR1: DHX15, SFPQ, NCL, TUBB, NONO, HSPA8, SF3B1, and HNRNPL (Binothman et al, 2017; Orecchini et al, 2017). Furthermore, we identified proteins that, like ADAR, bind the ACA11 transcript: SF3B1, PARP1, NCL, DDX21 and ILF3 ( Figure 1D, S3C ) (Chu et al, 2012).…”

Section: Resultsmentioning

confidence: 93%

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Freund

Sapiro

et al. 2019

Preprint

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13Adenosine-to-Inosine RNA editing is catalyzed by ADAR enzymes that deaminate adenosine to 14 inosine. While many RNA editing sites are known, few trans regulators have been identified. We 15 perform BioID followed by mass-spectrometry to identify trans regulators of ADAR1 and ADAR2 16 in HeLa and M17 neuroblastoma cells. We identify known and novel ADAR-interacting proteins. 17Using ENCODE data we validate and characterize a subset of the novel interactors as global or 18 site-specific RNA editing regulators. Our set of novel trans regulators includes all four members 19 of the DZF-domain-containing family of proteins: ILF3, ILF2, STRBP, and ZFR. We show that 20 these proteins interact with each ADAR and modulate RNA editing levels. We find ILF3 is a 21 global negative regulator of editing. This work demonstrates the broad roles RNA binding 22 proteins play in regulating editing levels and establishes DZF-domain containing proteins as a 23 group of highly influential RNA editing regulators. 24 25 47 the majority of ADAR1-regulated editing sites are found in repeat regions, ADAR2 is primarily 48 responsible for editing adenosines found in non-repeat regions, particularly in the brain (Tan et 49 al., 2017). ADAR2-regulated sites in non-repetitive regions include a number of editing events 50 that alter the protein-coding sequences of neuronal RNAs, including GluR2, which encodes a 51 glutamate receptor in which RNA editing is necessary for its proper function. Further 52 demonstrating its important role in neuronal editing, dysregulation of human ADAR2 is 53 associated with multiple neurological diseases, including amyotrophic lateral sclerosis, 54 astrocytoma and transient forebrain ischemia (Slotkin and Nishikura, 2013; Tran et al., 2019). 55Maintaining RNA editing levels is critical for human health, but how RNA editing levels are 56 regulated at specific editing sites across tissues and development is poorly understood. 58While RNA sequence and structure are critical determinants of editing levels, studies querying 59 tissue-specific and developmental-stage-specific editing levels show that the level of editing at 60 the same editing site can vary greatly between individuals and tissues. These changes do not 61 always correlate with ADAR mRNA or protein expression, suggesting a complex regulation of 62 editing events by factors other than ADAR proteins (Sapiro et al., 2019; Tan et al., 2017; 63 Wahlstedt et al., 2009). Recently, an analysis of proteins with an RNA-binding domain profiled 64 by ENCODE suggested that RNA-binding proteins play a role in RNA editing regulation. Further, 65 in mammals, a small number of trans regulators of editing have been identified through 66 functional experiments (Quinones-Valdez et al., 2019). Some of these trans regulators of editing 67 are site-specific, in that they affect editing levels at only a small subset of editing sites. These 68 include RNA binding proteins such as DHX15, HNRNPA2/B1, RPS14, TDP-43, Drosha and 69 Ro60 (Garncarz et al., 2013; Quinones-Valdez ...

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Section: Resultsmentioning

confidence: 93%

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Freund

Sapiro

et al. 2019

Preprint

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“…CPSF6 is wellestablished to regulate alternative cleavage and polyadenylation of cellular mRNA (1,4,5,60,61). Recently, an important role for CPSF6 is also described in cancer biology through its association with paraspeckles (8). Most noteworthy is the accumulating evidence showing key roles of CPSF6 during HIV-1 infection.…”

Section: Discussionmentioning

confidence: 99%

“…CFIm is also a component of paraspeckles, ribonucleoprotein complexes that are involved in regulating gene expression through nuclear retention of adenosine-to-inosine (A-to-I) edited RNA (6,7). A recent study suggested that through its association with paraspeckles, CPSF6 is involved in the regulation of breast cancer cell viability and tumorigenic capacity (8). In recent years, CPSF6 has also garnered a great deal of attention for its emerging role during the early steps of human immunodeficiency virus 1 (HIV-1) infection (9)(10)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

The HIV-1 capsid-binding host factor CPSF6 is post-transcriptionally regulated by the cellular microRNA miR-125b

Chaudhuri

Dash

Muthukumar

et al. 2020

Journal of Biological Chemistry

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Cleavage and polyadenylation specificity factor 6 (CPSF6) is a cellular protein involved in mRNA processing. Emerging evidence suggests that CPSF6 also plays key roles in HIV-1 infection, specifically during nuclear import and integration targeting. However, the cellular and molecular mechanisms that regulate CPSF6 expression are largely unknown. In this study, we report a post-transcriptional mechanism that regulates CPSF6 via the cellular microRNA miR-125b. An in silico analysis revealed that the 3′UTR of CPSF6 contains a miR-125b–binding site that is conserved across several mammalian species. Because miRNAs repress protein expression, we tested the effects of miR-125b expression on CPSF6 levels in miR-125b knockdown and over-expression experiments, revealing that miR-125b and CPSF6 levels are inversely correlated. To determine whether miR-125b post-transcriptionally regulates CPSF6, we introduced the 3′UTR of CPSF6 mRNA into a luciferase reporter and found that miR-125b negatively regulates CPSF6 3′UTR-driven luciferase activity. Accordingly, mutations in the miR-125b seed sequence abrogated the regulatory effect of the miRNA on the CPSF6 3′UTR. Finally, pulldown experiments demonstrated that miR-125b physically interacts with CPSF6 3′UTR. Interestingly, HIV-1 infection down-regulated miR-125b expression concurrent with up-regulation of CPSF6. Notably, miR-125b down-regulation in infected cells was not due to reduced pri-miRNA or pre-miRNA levels. However, miR-125b down-regulation depended on HIV-1 reverse transcription but not viral DNA integration. These findings establish a post-transcriptional mechanism that controls CPSF6 expression and highlight a novel function of miR-125b during HIV-host interaction.

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“…The beads were washed three times with IP buffer. 14 The level of IPenriched NUDT21 was measured by Western blotting.…”

Section: Immunoprecipitation (Ip)mentioning

confidence: 99%

<p>NUDT21 Suppresses Breast Cancer Tumorigenesis Through Regulating CPSF6 Expression</p>

Asan¹,

Liu²,

Guo³

et al. 2020

CMAR

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Background: NUDT21, an RNA binding protein, has been reported to play an important role in the regulation of multiple biological responses. Detection of NUDT21 expression may lead to the identification of a novel marker for breast cancer. Purpose: The aim of this study was to investigate the clinical significance and functional role of NUDT21 in breast cancer. Methods: The protein expression of NUDT21 was examined by immunohistochemistry (IHC) in 100 paraffin-embedded, archived breast cancer samples and 100 benign breast tissues. Then, the correlations between the NUDT21 expression and clinicopathologic characteristics and prognoses of the breast cancer patients were analyzed. In addition, the function of NUDT21 in breast cancer cell lines was detected by the methyl thiazolyl tetrazolium, colony formation and transwell assays. Finally, mass spectrometry analysis and Western blotting were used to identify the proteins that interact directly with NUDT21. Results: IHC analysis revealed that the expression of NUDT21 was significantly lower in breast cancer tissues compared with benign breast disease tissues. The correlation analysis revealed that low expression of NUDT21 was positively correlated with tumor size, lymph node metastasis, and TNM stage. Also, Kaplan-Meier survival curves showed that patients with lower NUDT21 expression had shorter overall survival and relapse-free survival compared with higher NUDT21 expression. In addition, the knockdown of NUDT21 enhanced cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT). Consistently, the overexpression of NUDT21 inhibited cell proliferation, migration, invasion, and EMT. In addition, NUDT21 directly interacted with CPSF6 and negatively regulated its expression. Moreover, the knockdown of CPSF6 reversed NUDT21 expression-induced cancer cell migration and invasion. Conclusion: NUDT21 might play a tumor-suppressive role by inhibiting cell proliferation and invasion via the NUDT21/CPSF6 signaling pathway in breast cancer cells.

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CPSF6 is a Clinically Relevant Breast Cancer Vulnerability Target

Cited by 45 publications

References 38 publications

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

The HIV-1 capsid-binding host factor CPSF6 is post-transcriptionally regulated by the cellular microRNA miR-125b

<p>NUDT21 Suppresses Breast Cancer Tumorigenesis Through Regulating CPSF6 Expression</p>

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