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J Hematol Oncol ; 11(1): 95, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30016968


BACKGROUND: Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin-proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC. METHODS: Immunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression. RESULTS: Ube2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC. CONCLUSIONS: Our study functionally links Ube2v1, an E2 member in the ubiquitin-proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients.

Neoplasias Colorretais/metabolismo , Sirtuína 1/metabolismo , Fatores de Transcrição/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Autofagia/fisiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Epigênese Genética , Transição Epitelial-Mesenquimal , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Ubiquitinação
Oncotarget ; 9(15): 12035-12049, 2018 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-29552291


The pathogenesis and key functional molecules involved in inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) remain unclear. Here, we reported that Erbin, a protein required for the polarity of epithelial cells, is conserved across species and highly expressed in the intestinal mucosa in mice and zebrafish. Pathologically, Erbin expression in the intestinal mucosa was significantly decreased in DSS induced acute colitis mice, IL-10 deficient mice and clinical biopsy specimens from patients with ulcerative colitis. Moreover, Erbin deficient mice are more susceptible to experimental colitis, exhibiting more severe intestinal barrier disruption, with increased histological scores and excessive production of proinflammatory cytokines. Mechanistically, Erbin deficiency or knockdown significantly exacerbated activation of autophagic program and autophagic cell death in vivo and in vitro. And, inhibition of autophagy by Chloroquine attenuates excessive inflammatory response in the DSS-induced colitis mouse model of Erbin deletion. Generally, our study uncovers a crucial role of Erbin in autophagic cell death and IBD, giving rise to a new strategy for IBD therapy by inhibiting excessive activation of autophagy and autophagic cell death.