PIWIL2 suppresses Siah2-mediated degradation of HDAC3 and facilitates CK2α-mediated HDAC3 phosphorylation

Zhang, Yingying; Zheng, Xulei; Tan, Hao; Lu, Yilu; Tao, Dachang; Ma, Yongxin

doi:10.1038/s41419-018-0462-8

Cited by 16 publications

(11 citation statements)

References 39 publications

(45 reference statements)

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“…It is suggested that the phosphorylation of HDAC3 may cause a conformational change, leading to a more active conformation. Zhang et al showed that P-element induced wimpy testis-like (PIWIL)-2 stabilizes HDAC3 by inhibiting E3 ubiquitin-ligase seven in absentia homolog 2 -mediated degradation through casein kinase 2-mediated HDAC3 phosphorylation, thereby accelerating the proliferation of p53-positive cancer cells, followed by a decrease in p21 expression [35]. Another study demonstrated that the phosphatase and tensin homolog-induced putative kinase 1-mediated phosphorylation of HDAC3 results in the suppression of dopaminergic neuronal cell death through an increase in the deacetylase activity via blockage of the HDAC3 cleavage in response to oxidative stress [19].…”

Section: Discussionmentioning

confidence: 99%

EGFR–c-Src-Mediated HDAC3 Phosphorylation Exacerbates Invasion of Breast Cancer Cells

Kwak

Seo

Sung

et al. 2019

Cells

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Breast cancer is one of the leading causes of morbidity and mortality among women. Epidermal growth factor receptor (EGFR) and proto-oncogene tyrosine-protein kinase Src (c-Src) are critical components of the signaling pathways that are associated with breast cancer. However, the regulatory mechanism of histone deacetylase 3 (HDAC3) in these pathways remains unclear. Using the Net Phos 3.1 program for the analysis of kinase consensus motifs, we found two c-Src-mediated putative phosphorylation sites, tyrosine (Tyr, Y)-328 and Y331 on HDAC3, and generated a phospho-specific HDAC3 antibody against these sites. c-Src-mediated phosphorylation was observed in the cells expressing wild-type HDAC3 (HDAC3WT), but not in cells overexpressing phosphorylation-defective HDAC3 (HDAC3Y328/331A). Phosphorylated HDAC3 showed relatively higher deacetylase activity, and PP2, which is a c-Src inhibitor, blocked HDAC3 phosphorylation and reduced its enzymatic activity. EGF treatment resulted in HDAC3 phosphorylation in both MDA-MB-231 and EGFR-overexpressing MCF7 (MCF7-EGFR) cells, but not in MCF7 cells. Total internal reflection fluorescence analysis showed that HDAC3 was recruited to the plasma membrane following EGF stimulation. HDAC3 inhibition with either c-Src knockdown or PP2 treatment significantly ameliorated the invasiveness of breast cancer cells. Altogether, our findings reveal an EGF signaling cascade involving EGFR, c-Src, and HDAC3 in breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

EGFR–c-Src-Mediated HDAC3 Phosphorylation Exacerbates Invasion of Breast Cancer Cells

Kwak

Seo

Sung

et al. 2019

Cells

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“…2e). Siah2 ubiquitinates most of its interacting partners and marks them for proteasome-mediated degradation [27,28]. To assess the ubiquitination status of MRCKβ in infected cells, MKN45 cells were treated with 50 µM MG132, a proteasomal inhibitor, along with H. pylori infection for 12 h at 200 MOI.…”

Section: Mrckβ Protein Is Downregulated In H Pylori-infected Gecsmentioning

confidence: 99%

Helicobacter pylori-induced gastric cancer is orchestrated by MRCKβ-mediated Siah2 phosphorylation

et al. 2021

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Background Helicobacter pylori-mediated gastric carcinogenesis is initiated by a plethora of signaling events in the infected gastric epithelial cells (GECs). The E3 ubiquitin ligase seven in absentia homolog 2 (Siah2) is induced in GECs in response to H. pylori infection. Posttranslational modifications of Siah2 orchestrate its function as well as stability. The aim of this study was to evaluate Siah2 phosphorylation status under the influence of H. pylori infection and its impact in gastric cancer progression. Methods H. pylori-infected various GECs, gastric tissues from H. pylori-infected GC patients and H. felis-infected C57BL/6 mice were evaluated for Siah2 phosphorylation by western blotting or immunofluorescence microscopy. Coimmunoprecipitation assay followed by mass spectrometry were performed to identify the kinases interacting with Siah2. Phosphorylation sites of Siah2 were identified by using various plasmid constructs generated by site-directed mutagenesis. Proteasome inhibitor MG132 was used to investigate proteasome degradation events. The importance of Siah2 phosphorylation on tumorigenicity of infected cells were detected by using phosphorylation-null mutant and wild type Siah2 stably-transfected cells followed by clonogenicity assay, cell proliferation assay, anchorage-independent growth and transwell invasion assay. Results Siah2 was phosphorylated in H. pylori-infected GECs as well as in metastatic GC tissues at residues serine6 (Ser6) and threonine279 (Thr279). Phosphorylation of Siah2 was mediated by MRCKβ, a Ser/Thr protein kinase. MRCKβ was consistently expressed in uninfected GECs and noncancer gastric tissues but its level decreased in infected GECs as well as in metastatic tissues which had enhanced Siah2 expression. Infected murine gastric tissues showed similar results. MRCKβ could phosphorylate Siah2 but itself got ubiquitinated from this interaction leading to the proteasomal degradation of MRCKβ and use of proteasomal inhibitor MG132 could rescue MRCKβ from Siah2-mediated degradation. Ser6 and Thr279 phosphorylated-Siah2 was more stable and tumorigenic than its non-phosphorylated counterpart as revealed by the proliferation, invasion, migration abilities and anchorage-independent growth of stable-transfected cells. Conclusions Increased level of Ser6 and Thr279-phosphorylated-Siah2 and downregulated MRCKβ were prominent histological characteristics of Helicobacter-infected gastric epithelium and metastatic human GC. MRCKβ-dependent Siah2 phosphorylation stabilized Siah2 which promoted anchorage-independent survival and proliferative potential of GECs. Phospho-null mutants of Siah2 (S6A and T279A) showed abated tumorigenicity.

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“…It has been shown that the nuclear PIWI/piRNA complexes take part in the chromatin modification pathway by manipulating DNA methylation and/or histone methylation around the targeted regions (49). Recently, it was reported that PIWIL2 not only stabilizes HDAC3 by competing with E3 ubiquitin ligase Siah2 but also enhances its phosphorylation via CK2a in human tumor cell lines (76). This work connects PIWI proteins with HDACs in human somatic cells.…”

Section: Suv39h1mentioning

confidence: 90%

PIWIL4 Maintains HIV-1 Latency by Enforcing Epigenetically Suppressive Modifications on the 5′ Long Terminal Repeat

Jing

Yang

et al. 2020

J Virol

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Although substantial progress has been made in depicting the molecular pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection, the comprehensive mechanism of HIV-1 latency and the most promising therapeutic strategies to effectively reactivate the HIV-1 latent reservoir to achieve a functional cure for AIDS remain to be systematically illuminated. Here, we demonstrated that piwi (P element-induced Wimpy)-like RNA-mediated gene silencing 4 (PIWIL4) played an important role in suppressing HIV-1 transcription and contributed to the latency state in HIV-1-infected cells through its recruitment of various suppressive factors, including heterochromatin protein 1α/β/γ, SETDB1, and HDAC4. The knockdown of PIWIL4 enhanced HIV-1 transcription and reversed HIV-1 latency in both HIV-1 latently infected Jurkat T cells and primary CD4+ T lymphocytes and resting CD4+ T lymphocytes from HIV-1-infected individuals on suppressive combined antiretroviral therapy (cART). Furthermore, in the absence of PIWIL4, HIV-1 latently infected Jurkat T cells were more sensitive to reactivation with vorinostat (suberoylanilide hydroxamic acid, or SAHA), JQ1, or prostratin. These findings indicated that PIWIL4 promotes HIV-1 latency by imposing repressive marks at the HIV-1 5′ long terminal repeat. Thus, the manipulation of PIWIL4 could be a novel strategy for developing promising latency-reversing agents (LRAs). IMPORTANCE HIV-1 latency is systematically modulated by host factors and viral proteins. During this process, the suppression of HIV-1 transcription plays an essential role in promoting HIV-1 latency. In this study, we found that PIWIL4 repressed HIV-1 promoter activity and maintained HIV-1 latency. In particular, we report that PIWIL4 can regulate gene expression through its association with the suppressive activity of HDAC4. Therefore, we have identified a new function for PIWIL4: it is not only a suppressor of endogenous retrotransposons but also plays an important role in inhibiting transcription and leading to latent infection of HIV-1, a well-known exogenous retrovirus. Our results also indicate a novel therapeutic target to reactivate the HIV-1 latent reservoir.

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PIWIL2 suppresses Siah2-mediated degradation of HDAC3 and facilitates CK2α-mediated HDAC3 phosphorylation

Cited by 16 publications

References 39 publications

EGFR–c-Src-Mediated HDAC3 Phosphorylation Exacerbates Invasion of Breast Cancer Cells

EGFR–c-Src-Mediated HDAC3 Phosphorylation Exacerbates Invasion of Breast Cancer Cells

Helicobacter pylori-induced gastric cancer is orchestrated by MRCKβ-mediated Siah2 phosphorylation

PIWIL4 Maintains HIV-1 Latency by Enforcing Epigenetically Suppressive Modifications on the 5′ Long Terminal Repeat

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