RNA Helicase DDX5 Inhibits Reprogramming to Pluripotency by miRNA-Based Repression of RYBP and its PRC1-Dependent and -Independent Functions

Li, Huanhuan; Lai, Ping Shan; Jia, Jinping; Song, Yawei; Xia, Qing; Huang, Kainian; He, Na; Ping, Wangfang; Chen, Jiayu; Yang, Zhongzhou; Li, Jiao; Yao, Maojin; Dong, Xiaohan; Zhao, Ji‐Cheng; Hou, Chaoqi; Esteban, Miguel A.; Gao, Shaorong; Pei, Duanqing; Hutchins, Andrew P.; Yao, Hongjie

doi:10.1016/j.stem.2016.12.002

Cited by 81 publications

(69 citation statements)

References 46 publications

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“…DDX5 plays an important role in miRNA processing. For example, DDX5 inhibits reprogramming to pluripotency through its role in producing mature miR‐125b . Further study is required to determine whether DDX5 regulation of autophagy involves miRNA processing.…”

Section: Discussionmentioning

confidence: 99%

“…(25) Recently, DDX5 has been reported to act as a reprogramming roadblock, regulating pluripotency gene expression through its role in miRNA processing. (26) HBV-associated HCC patients exhibit reduced DDX5 expression (25) ; other studies have shown HCCs with reduced autophagy and accumulation of p62 (3,27) to associate with poor prognosis after tumor resection. (1) These findings suggest a link between DDX5 downregulation and autophagy.…”

mentioning

confidence: 93%

“…Hepatitis B virus (HBV)‐associated HCCs exhibited a strong negative correlation between DDX5 expression, pluripotency gene expression, and liver tumor differentiation . Recently, DDX5 has been reported to act as a reprogramming roadblock, regulating pluripotency gene expression through its role in miRNA processing . HBV‐associated HCC patients exhibit reduced DDX5 expression; other studies have shown HCCs with reduced autophagy and accumulation of p62 to associate with poor prognosis after tumor resection .…”

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confidence: 99%

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DEAD Box Protein 5 Inhibits Liver Tumorigenesis by Stimulating Autophagy via Interaction with p62/SQSTM1

Zhang

Zhu

et al. 2019

Hepatology

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In hepatocellular carcinoma (HCC), dysregulated expression of DDX5 (DEAD box protein 5) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. Here we present evidence to show that, by interacting with autophagic receptor p62, DDX5 promotes autophagy and suppresses tumorigenesis. DDX5 inversely correlated with p62/sequestosome 1 (SQSTM1) expression in hepatitis B virus (HBV)‐associated and non‐HBV‐associated HCCs. Patients with low DDX5 expression showed poor prognosis after tumor resection. We found that DDX5 overexpression induced, while DDX5 knockdown attenuated, autophagic flux in HepG2 and Huh7 cells. DDX5 promoted p62 degradation and markedly reduced the half‐life of p62. Moreover, DDX5 overexpression dramatically reduced, while DDX5 knockdown promoted, cancer cell growth and tumorigenesis in vitro and in vivo. We found that DDX5 bound to p62 and interfered with p62/TRAF6 (tumor necrosis factor receptor–associated factor 6) interaction. Further findings revealed that the N‐terminal domain of DDX5, involved in the interaction with p62, was sufficient to induce autophagy independent of its RNA binding and helicase activity. DDX5 overexpression decreased p62/TRAF6‐mediated lysine 63‐linked ubiquitination of mammalian target of rapamycin (mTOR) and subsequently inhibited the mTOR signaling pathway. Knockdown of TRAF6 blocked DDX5‐induced autophagy. Furthermore, we showed that miR‐17‐5p downregulated DDX5 and impaired autophagy. Inhibition of miR‐17‐5p promoted autophagic flux and suppressed tumor growth in HCC xenograft models. Conclusion: Our findings define a noncanonical pathway that links miR‐17‐5p, DDX5, p62/TRAF6, autophagy, and HCC. These findings open an avenue for the treatment of HCC.

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Section: Discussionmentioning

confidence: 99%

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confidence: 93%

mentioning

confidence: 99%

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DEAD Box Protein 5 Inhibits Liver Tumorigenesis by Stimulating Autophagy via Interaction with p62/SQSTM1

Zhang

Zhu

et al. 2019

Hepatology

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“…This study indicated the existence of a RYBP‐miR‐29 feedback loop that may play a key role in skeletal myogenesis . During reprogramming, loss of DDX5 acted as a promoter of somatic cell reprogramming by repressing miR‐125b expression, which in turn, resulted in the RYBP up‐regulation . Intriguingly, enhanced RYBP not only suppressed lineage‐specific genes by increasing monoubiquitination of histone H2A at lysine‐119 (H2AK119ub1) levels through PRC1, but also activated pluripotency‐promoting genes by facilitating the recruitment of OCT4 to the Kdm2b promoter .…”

Section: The Roles Of Rybp In Developmentmentioning

confidence: 92%

“…During reprogramming, loss of DDX5 acted as a promoter of somatic cell reprogramming by repressing miR-125b expression, which in turn, resulted in the RYBP up-regulation [15]. Intriguingly, enhanced RYBP not only suppressed lineage-specific genes by increasing monoubiquitination of histone H2A at lysine-119 (H2AK119ub1) levels through PRC1, but also activated pluripotency-promoting genes by facilitating the recruitment of OCT4 to the Kdm2b promoter [15]. Thus, this study suggested that DDX5 controlled reprogramming through the PRC1-dependent and PRC1-independent functions of RYBP.…”

Section: The Roles Of Rybp In Developmentmentioning

confidence: 99%

Multiple roles of Ring 1 and YY1 binding protein in physiology and disease

Zhan

Wang

et al. 2018

J Cellular Molecular Medi

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IntroductionThe roles of RYBP in development The roles of RYBP in the regulation of gene expression through the PcG complex and binding with transcriptional factorsThe roles of RYBP in the apoptosis The roles of RYBP in the cancer Concluding remarks Conflict of interest AbstractRing 1 and YY1 binding protein (RYBP) was first identified in 1999, and its structure includes a conserved Npl4 Zinc finger motif at the N-terminus, a central region that is characteristically enriched with arginine and lysine residues and a C-terminal region enriched with serine and threonine amino acids. Over nearly 20 years, multiple studies have found that RYBP functions as an organ developmental adaptor. There is also evidence that RYBP regulates the expression of different genes involved in various aspects of biological processes, via a mechanism that is dependent on interactions with components of PcG complexes and/or through binding to different transcriptional factors. In addition, RYBP interacts directly or indirectly with apoptosis-associated proteins to mediate anti-apoptotic or pro-apoptotic activity in both the cytoplasm and nucleus of various cell types. Furthermore, RYBP has also been shown to act as tumour suppressor gene in different solid tumours, but as an oncogene in lymphoma and melanoma. In this review, we summarize our current understanding of the functions of this multifaceted RYBP in physiological and pathological conditions, including embryonic development, apoptosis and cancer, as well as its role as a component of polycomb repressive complex 1.

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The DDX5/Dbp2 subfamily of DEAD‐box RNA helicases

2018

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The mammalian DEAD-box RNA helicase DDX5, its paralog DDX17, and their orthologs in Saccharomyces cerevisiae and Drosophila melanogaster, namely Dbp2 and Rm62, define a subfamily of DEAD-box proteins. Members from this subfamily share highly conserved protein sequences and cellular functions. They are involved in multiple steps of RNA metabolism including mRNA processing, microRNA processing, ribosome biogenesis, RNA decay, and regulation of long non-coding RNA activities. The DDX5/Dbp2 subfamily is also implicated in transcription regulation, cellular signalling pathways, and energy metabolism. One emerging theme underlying the diverse cellular functions is that the DDX5/Dbp2 subfamily of DEAD-box helicases act as chaperones for complexes formed by RNA molecules and proteins (RNP) in vivo. This RNP chaperone activity governs the functions of various RNA species through their life time. Importantly, mammalian DDX5 and DDX17 are involved in cancer progression when overexpressed through alteration of transcription and signalling pathways, meaning that they are possible targets for cancer therapy.

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RNA Helicase DDX5 Inhibits Reprogramming to Pluripotency by miRNA-Based Repression of RYBP and its PRC1-Dependent and -Independent Functions

Cited by 81 publications

References 46 publications

DEAD Box Protein 5 Inhibits Liver Tumorigenesis by Stimulating Autophagy via Interaction with p62/SQSTM1

DEAD Box Protein 5 Inhibits Liver Tumorigenesis by Stimulating Autophagy via Interaction with p62/SQSTM1

Multiple roles of Ring 1 and YY1 binding protein in physiology and disease

The DDX5/Dbp2 subfamily of DEAD‐box RNA helicases

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