Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4A DCAF1 to promote colon cancer development

Ren, Weiguo; Shen, Shourong; Sun, Zhenqiang; Shu, Ping; Shen, Xiaohua; Bu, Chibin; Ai, Feiyan; Zhang, Xuemei; Tang, Anliu; Liu, Tian; Li, Guiyuan; Li, Xiayu; Ma, Jian

doi:10.1016/j.canlet.2016.02.055

Cited by 34 publications

(44 citation statements)

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“…At present, numerous proteins have been reported to be ubiquitinated by CUL4A including p53, p21, p27, DICER, and LATS1 [32]. Previous studies have shown that inflammation-induced Jak-STAT3 signaling triggers the ubiquitination of DICER1 in cytoplasm by CUL4A to promote the development of colon cancer [33]. Although CUL4A is predominantly located in the cytoplasm, a fraction of CUL4A protein resides in the nucleus and mediates nucleosome reassembly [34–36].…”

Section: Resultsmentioning

confidence: 99%

A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of LATS1

et al. 2017

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BackgroundHepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and tumor recurrence and metastasis are major factors that contribute to the poor outcome of patients with HCC. Long noncoding RNAs (lncRNAs) are known to regulate different tumorigenic processes, and a growing body of evidence indicates that Hippo kinase signaling is inactivated in many cancers. However, the upstream lncRNA regulators of Hippo kinase signaling in HCC are poorly understood.MethodsUsing a lncRNA microarray, we identified a novel lncRNA, uc.134, whose expression was significantly decreased in the highly aggressive HCC cell line HCCLM3 compared with MHCC97L cells. Furthermore, we evaluated uc.134 expression in clinical samples using in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The full-length transcript of uc.134 was confirmed using rapid amplification of cDNA ends (RACE) analyses. To investigate the biological function of uc.134, we performed gain-of-function and loss-of-function studies both in vitro and in vivo. The underlying mechanisms of uc.134 in HCC were investigated using RNA pulldown, RNA immunoprecipitation, ubiquitination assays, Western blotting, mRNA microarray analyses, and qRT-PCR analyses.ResultsThe ISH assay revealed that uc.134 expression was significantly decreased in 170 paraffin-embedded samples from patients with HCC compared with adjacent tissues and uc.134 expression directly correlated with patient prognosis. Furthermore, we defined a 1867-bp full-length transcript of uc.134 using 5′- and 3′-RACE analysis. The overexpression of uc.134 inhibited HCC cell proliferation, invasion, and metastasis in vitro and in vivo, whereas the knockdown of uc.134 produced the opposite results. Furthermore, we confirmed that uc.134 (1408–1867 nt) binds to CUL4A (592–759 aa region) and inhibits its nuclear export. Moreover, we demonstrated that uc.134 inhibits the CUL4A-mediated ubiquitination of LATS1 and increases YAPS127 phosphorylation to silence the target genes of YAP. Finally, a positive correlation between uc.134, LATS1, and pYAPS127 was confirmed in 90 paraffin-embedded samples by ISH and immunohistochemical staining.ConclusionsOur study identifies that a novel lncRNA, uc.134, represses hepatocellular carcinoma progression by inhibiting the CUL4A-mediated ubiquitination of LATS1 and increasing YAPS127 phosphorylation. The use of this lncRNA may offer a promising treatment approach by inhibiting YAP and activating Hippo kinase signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0449-4) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of LATS1

et al. 2017

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“…The importance of inflammation and immunobiology in malignant progression has become a recent focus of attention . Previous studies have identified elevated p‐STAT3 as a prognostic factor for various cancers, including CRC, highlighting STAT3 as a major molecular bridge between inflammation and carcinogenesis. In our study, low‐grade intestinal inflammation and STAT3 signaling activation were observed in the CA group, all of which were abolished by antibiotics.…”

Section: Discussionmentioning

confidence: 99%

Interplay between bile acids and the gut microbiota promotes intestinal carcinogenesis

Sinan

Dong

Liu

et al. 2019

Molecular Carcinogenesis

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The gut microbiota and the bile acid pool play pivotal roles in maintaining intestinal homeostasis. Bile acids are produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. Gut dysbiosis has been reported to be associated with colorectal cancer. However, the interplay between bile acid metabolism and the gut microbiota during intestinal carcinogenesis remains unclear. In the present study, we investigated the potential roles of bile acids and the gut microbiota in the cholic acid (CA; a primary bile acid)‐induced intestinal adenoma‐adenocarcinoma sequence. Apc min/+ mice, which spontaneously develop intestinal adenomas, were fed a diet supplemented with 0.4% CA for 12 weeks. Mice that were fed a normal diet were regarded as untreated controls. In CA‐treated Apc min/+ mice, the composition of the gut microbiota was significantly altered, and CA was efficiently transformed into deoxycholic acid (a secondary bile acid) by the bacterial 7α‐dehydroxylation reaction. The intestinal adenoma‐adenocarcinoma sequence was observed in CA‐treated Apc min/+ mice and was accompanied by an impaired intestinal barrier function and IL‐6/STAT3‐related low‐grade inflammation. More importantly, microbiota depletion using an antibiotic cocktail globally compromised CA‐induced intestinal carcinogenesis, suggesting a leading role for the microbiota during this process. Overall, our data suggested that the crosstalk between bile acids and the gut microbiota mediated intestinal carcinogenesis, which might provide novel therapeutic strategies against intestinal tumor development.

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“…STAT3 serves an important role in embryonic development and the function of normal cells (9). The abnormal expression and activation of STAT3 was revealed in numerous types of tumor, suggesting that it may promote the development of the tumor (9,25).…”

Section: Discussionmentioning

confidence: 99%

“…In order to apply these results to the therapeutic treatment of tumors, it is necessary to evaluate a potential association between the activation of STAT3 and disease progression, whether tumors with high phosphorylation level and heterogeneity of the STAT3 tyrosine residue are more sensitive to targeted therapy, the role that other types of STATs serve in the tumor microenvironment, and whether blocking the JAK2/STAT3 signal pathway may activate other signal pathways through a crosstalk effect and thereby result in drug resistance of tumor cells (9,27). With the continuous improvement of in vitro and clinical tests, the JAK2/STAT3 signaling pathway is expected to become a novel target for the treatment of CRC without combination with other drugs, in order to decrease the risk of drug resistance and improve the quality of In summary, the present study demonstrated that treatment with dihydroar temisinin decreased cell viability, induced apoptosis, increased caspase-3/9 activities and upregulated BAX protein expression, which is mediated by the PARP/MAPK and JAK2/STAT3 signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…The activation of STAT3 serves an important function in tumor progression, particularly in tumors associated with chronic inflammation, including inflammatory colitis-associated CRC, liver cancer and pancreatic cancer (8). Sustained activation of JAK2/STAT3 is associated with tumorigenesis, differentiation, proliferation, apoptosis, angiogenesis, recruitment of immune cells and metastasis of tumors (9).…”

Section: Introductionmentioning

confidence: 99%

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Dihydroartemisinin increases apoptosis of colon cancer cells through targeting Janus kinase 2/signal transducer and activator of transcription 3 signaling

et al. 2017

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Abstract. As a derivative of artemisinin, dihydroartemisinin is effective in the treatment of malaria. Dihydroartemisinin has been identified to possess inhibitory effects in numerous types of animal model with tumors, indicating that it has an antineoplastic effect. The aim of the present study was to analyze the potential anticancer effects of dihydroartemisinin, particularly its effect on apoptosis of colon cancer cells. In the present study, it was identified that dihydroartemisinin inhibited cell viability, promoted cell apoptosis, increased B-cell lymphoma-2-associated X-protein expression, increased caspase-3/9 activities, decreased poly(ADP-ribose) polymerase levels, decreased phosphorylation of extracellular-signal-regulated kinase, and increased phosphorylation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase in colon cancer cells. Conversely, the phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) was suppressed by dihydroartemisinin in colon cancer cells. These results demonstrate that the potential anticancer effects of dihydroartemisinin may increase apoptosis of colon cancer cells through targeting JAK2/STAT3 signaling.

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Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4A DCAF1 to promote colon cancer development

Cited by 34 publications

References 54 publications

A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of LATS1

A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of LATS1

Interplay between bile acids and the gut microbiota promotes intestinal carcinogenesis

Dihydroartemisinin increases apoptosis of colon cancer cells through targeting Janus kinase 2/signal transducer and activator of transcription 3 signaling

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