PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer

Yang, Li; Yao, Xing; Wang, Xu; Hu, Bingtao; Zhao, Xin; Zhang, Hongyan; Han, Fuyi; Geng, Nanxi; Wang, Fei; Li, Yanshu; Li, Jiabin; Jin, Feng; Li, Feng

doi:10.1016/j.celrep.2021.110127

Cited by 16 publications

(10 citation statements)

References 37 publications

(54 reference statements)

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“…DDX5 itself has been implicated in the development of various types of cancers 24 , 37 , 38 , 62 , 63 . Reports suggest a strong connection between the development of various cancers and post translational modifications such as O-GlcNAcylation, sumoylation, and phosphorylation) of the DDX5 protein 13 , 64 , 65 . Previous investigations in our laboratory have demonstrated that, in contrast to the bronchial epithelial cell line HBEC-3KT (HBEC), the levels of DDX5 protein are significantly elevated in the chemosensitive H69 and chemoresistant H69AR SCLC cell lines 5 .…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Supinoxin blocks Small Cell Lung Cancer Progression by Inhibiting Mitochondrial Respiration through the RNA Helicase DDX5

Tran,

Das,

Russon

et al. 2024

Preprint

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DDX5 is a DEAD-box RNA helicase that is overexpressed and implicated in progression of several cancers 1–4. One of these is small cell lung cancer (SCLC). Our laboratory has demonstrated that the RNA helicase DDX5 is essential for the invasive growth of SCLC and mitochondrial respiration 5. SCLC is an extremely lethal, recalcitrant tumor 6,7, causing 250,000 deaths annually worldwide 8 and currently lacking effective treatments 9,10. Supinoxin (RX 5902), a compound having anti-cancer activity 11, is a known target of phosphor-DDX5 12,13; Supinoxin blocks the interaction between β-catenin and phosphor-DDX5 13, thereby releasing β-catenin and allowing its degradation. In an effort to repurpose Supinoxin for treatment of SCLC, we conducted a series of in vitro and in vivo experiments. Supinoxin has been observed to impede the proliferation of H69AR cell lines. Additionally, Supinoxin has the potential to mitigate both the growth of H69AR xenograft tumors and SCLC PDX tumors in vivo at a dosage of 70mg/kg in immunocompromised mice. The findings indicate that the administration of Supinoxin is effective in suppressing the growth of tumors and enhancing the survival rate of mice with SCLC tumors. Subsequently, an effort was made to explore the molecular pathways involved in the activity of Supinoxin in Small Cell Lung Cancer (SCLC) cells. Surprisingly, we did not see any decrease in β-catenin levels or relocalization from the cytoplasm upon Supinoxin treatment. Moreover, we did not observe any decrease in the expression levels of β-catenin target genes thereby contradicting the current model. Based on our current data we found that the current model of Supinoxin activity is inaccurate. Additional investigations were conducted to explore the mechanisms by which Supinoxin affects small cell lung cancer (SCLC). Treatment with Supinoxin induced mitochondrial dysfunction in the chemoresistant small cell lung cancer (SCLC) cell line H69AR. The latter was evidenced by down-regulation of genes associated with oxidative phosphorylation. Thus, Supinoxin is a new therapeutic agent for small cell lung cancer (SCLC).

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Section: Discussionmentioning

confidence: 99%

RETRACTED: Supinoxin blocks Small Cell Lung Cancer Progression by Inhibiting Mitochondrial Respiration through the RNA Helicase DDX5

Tran,

Das,

Russon

et al. 2024

Preprint

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“…The T69, T446, T564, S557, Y593, and Y595 sites of DDX5 can be phosphorylated. T69-phosphorylated DDX5 by PAK5 increases binding to the Drosha/DGCR8 complex to facilitate miR-10b production, promoting breast cancer cell proliferation and migration ( 112 ). S557-phosphorylated DDX5 is a microtubule motor that binds calmodulin (CaM) to position CaM at the front of metastatic cells and thus promotes cell metastasis ( 113 ).…”

Section: Posttranslational Modifications Of Ddx5 and Ddx17 In Cancermentioning

confidence: 99%

DDX5 and DDX17—multifaceted proteins in the regulation of tumorigenesis and tumor progression

Sun

Yan

et al. 2022

Front. Oncol.

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DEAD-box (DDX)5 and DDX17, which belong to the DEAD-box RNA helicase family, are nuclear and cytoplasmic shuttle proteins. These proteins are expressed in most tissues and cells and participate in the regulation of normal physiological functions; their abnormal expression is closely related to tumorigenesis and tumor progression. DDX5/DDX17 participate in almost all processes of RNA metabolism, such as the alternative splicing of mRNA, biogenesis of microRNAs (miRNAs) and ribosomes, degradation of mRNA, interaction with long noncoding RNAs (lncRNAs) and coregulation of transcriptional activity. Moreover, different posttranslational modifications, such as phosphorylation, acetylation, ubiquitination, and sumoylation, endow DDX5/DDX17 with different functions in tumorigenesis and tumor progression. Indeed, DDX5 and DDX17 also interact with multiple key tumor-promoting molecules and participate in tumorigenesis and tumor progression signaling pathways. When DDX5/DDX17 expression or their posttranslational modification is dysregulated, the normal cellular signaling network collapses, leading to many pathological states, including tumorigenesis and tumor development. This review mainly discusses the molecular structure features and biological functions of DDX5/DDX17 and their effects on tumorigenesis and tumor progression, as well as their potential clinical application for tumor treatment.

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“…Given the prominent role of TLR2/4 in recognizing bacterial PAMPs and activating inflammation through the NF-κB pathway (Adelaja and Hoffmann, 2019 ; Meizlish et al, 2021 ), the TLR2/4 agonists LPS, FSL-1, and Pam3CSK4 were used to explore the mechanism through which DDX5 activated the TLR2/4/NF-κB pathway upon bacterial infection. Because the expression of DDX5 decreased following treatment with TLR2/4 agonists in both MEFs and mouse macrophages, we hypothesized that post-translational modifications, such as phosphorylation, SUMOylation, or ubiquitination could be involved in downregulating DDX5 upon bacterial infection (Clark et al, 2008 ; Li et al, 2021 ; Zheng et al, 2021 ). Indeed, we found DDX5 was translocated from the nucleus and targeted by an ER-localized E3 ligase Hrd1, which was the main E3 ligase responsible for degradation of nuclear proteins, such as USP15 and METTL14 (Lu et al, 2019 ; Wei et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

DDX5 inhibits inflammation by modulating m6A levels of TLR2/4 transcripts during bacterial infection

Xu,

Liu,

Zhi

et al. 2024

EMBO Rep

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DExD/H-box helicases are crucial regulators of RNA metabolism and antiviral innate immune responses; however, their role in bacteria-induced inflammation remains unclear. Here, we report that DDX5 interacts with METTL3 and METTL14 to form an m6A writing complex, which adds N6-methyladenosine to transcripts of toll-like receptor (TLR) 2 and TLR4, promoting their decay via YTHDF2-mediated RNA degradation, resulting in reduced expression of TLR2/4. Upon bacterial infection, DDX5 is recruited to Hrd1 at the endoplasmic reticulum in an MyD88-dependent manner and is degraded by the ubiquitin-proteasome pathway. This process disrupts the DDX5 m6A writing complex and halts m6A modification as well as degradation of TLR2/4 mRNAs, thereby promoting the expression of TLR2 and TLR4 and downstream NF-κB activation. The role of DDX5 in regulating inflammation is also validated in vivo, as DDX5- and METTL3-KO mice exhibit enhanced expression of inflammatory cytokines. Our findings show that DDX5 acts as a molecular switch to regulate inflammation during bacterial infection and shed light on mechanisms of quiescent inflammation during homeostasis.

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PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer

Cited by 16 publications

References 37 publications

RETRACTED: Supinoxin blocks Small Cell Lung Cancer Progression by Inhibiting Mitochondrial Respiration through the RNA Helicase DDX5

RETRACTED: Supinoxin blocks Small Cell Lung Cancer Progression by Inhibiting Mitochondrial Respiration through the RNA Helicase DDX5

DDX5 and DDX17—multifaceted proteins in the regulation of tumorigenesis and tumor progression

DDX5 inhibits inflammation by modulating m6A levels of TLR2/4 transcripts during bacterial infection

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