Ret finger protein-like 3 promotes tumor cell growth by activating telomerase reverse transcriptase expression in human lung cancer cells

Chen, Wangbing; Lu, Jianjun; Yu, Qin; Wang, Jingshu; Tian, Yun; Shi, Dingbo; Wang, Shusen; Xiao, Yao; Dai, Meng; Liu, Lu; Guo, Wei; Jin, Bilian; Xiao, Xia; Kang, Tie Bang; Huang, Wenlin; Deng, Wuguo

doi:10.18632/oncotarget.2557

Cited by 12 publications

(13 citation statements)

References 42 publications

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“… 52 A number of factors have been identified to regulate the activity of the hTERT promoter directly or indirectly. 53 , 54 , 55 To test if KMT2A anchored at the hTERT promoter to regulate its expression, ChIP assay was performed in melanoma cells. The results showed that the hTERT promoter region was amplified by PCR from the complexes immunoprecipitated by the antibody against KMT2A, but not from the complexes precipitated by the IgG negative control ( Figure 2e and f ).…”

Section: Resultsmentioning

confidence: 99%

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

et al. 2017

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Melanoma is an aggressive cutaneous malignancy, illuminating the exact mechanisms and finding novel therapeutic targets are urgently needed. In this study, we identified KMT2A as a potential target, which promoted the growth of human melanoma cells. KMT2A knockdown significantly inhibited cell viability and cell migration and induced apoptosis, whereas KMT2A overexpression effectively promoted cell proliferation in various melanoma cell lines. Further study showed that KMT2A regulated melanoma cell growth by targeting the hTERT-dependent signal pathway. Knockdown of KMT2A markedly inhibited the promoter activity and expression of hTERT, and hTERT overexpression rescued the viability inhibition caused by KMT2A knockdown. Moreover, KMT2A knockdown suppressed tumorsphere formation and the expression of cancer stem cell markers, which was also reversed by hTERT overexpression. In addition, the results from a xenograft mouse model confirmed that KMT2A promoted melanoma growth via hTERT signaling. Finally, analyses of clinical samples demonstrated that the expression of KMT2A and hTERT were positively correlated in melanoma tumor tissues, and KMT2A high expression predicted poor prognosis in melanoma patients. Collectively, our results indicate that KMT2A promotes melanoma growth by activating the hTERT signaling, suggesting that the KMT2A/hTERT signaling pathway may be a potential therapeutic target for melanoma.

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Section: Resultsmentioning

confidence: 99%

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

et al. 2017

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“…Since hTERT was approved to be involved in the growth of lung cancer cells [ 19 ], and RFPL3 and CBP had been shown to be able to up-regulate hTERT expression, we next tested the coordinated effect of RFPL3 and CBP on cell proliferation in lung cancer cells. The H1299 cells with RFPL3-stable overexpression were transfected with CBP-specific siRNA or treated with CBP inhibitor C464.…”

Section: Resultsmentioning

confidence: 99%

“…However, little is known about the underlying molecular mechanisms of the reactivation of hTERT during tumorigenesis for lung cancers. In our previous study, we discovered and identified RFPL3 as a novel hTERT promoter-binding protein which could upregulate hTERT activity in lung cancers [ 19 ]. We also showed that the inhibition of RFPL3 expression significantly suppressed lung cancer cell growth in vitro and in a xenograft mouse model in vivo .…”

Section: Introductionmentioning

confidence: 99%

RFPL3 and CBP synergistically upregulate hTERT activity and promote lung cancer growth

Chen

Xiao

et al. 2015

Oncotarget

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hTERT is the key component of telomerase and its overactivation contributes to maintaining telomere length and cell immortalization. Previously, we identified RFPL3 as a new transcription activator of hTERT in lung cancers. However, the exact mechanism of RFPL3 in mediating hTERT activation and its associated signal regulatory network remain unclear. In this study, we found that RFPL3 colocalized and interacted directly with CBP in the nucleus of lung cancer cells. Immunohistochemical analysis of tissue microarrays of lung cancers revealed the simultaneous overexpression of both RFPL3 and CBP predicted relatively poor prognosis. Furthermore, we confirmed their synergistic stimulation on hTERT expression and tumor cell growth. The binding of RFPL3 to hTERT promoter was reduced markedly when CBP was knocked down by its specific siRNA or suppressed by its inhibitor in lung cancer cells with stable overexpression of RFPL3. When one of the two proteins RFPL3 and CBP was upregulated or downregulated, whereas the another remains unchanged, hTERT expression and telomerase activity were activated or repressed accordingly. In the meantime, the growth of lung cancer cells was also promoted or attenuated accordingly. Furthermore, we also found that RFPL3 coordinated with CBP to upregulate hTERT through the CBP-induced acetylation of RFPL3 protein and their co-anchoring at hTERT promoter region. Collectively, our results reveal a new mechanism of hTERT regulation in lung cancer cells and suggest the RFPL3/CBP/hTERT signaling pathway may be a new targets for lung cancer treatment.

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“…Next, we tested whether RBFOX3 bound to the hTERT promoter by interacting with other transcription factors. To test this hypothesis, four hTERT promoter-binding proteins KLF4 25 , RFPL3 26 , CPSF4 27 and AP-2β 23 previously identified were tested using their corresponding specific antibodies by a co-immunoprecipitation assay in the flag-RBFOX3 overexpressing Hep3B and HepG2 cells. Surprisingly, RBFOX3 could be pulled down by anti-AP-2β antibody ( Figure 6 A ).…”

Section: Resultsmentioning

confidence: 99%

RBFOX3 Promotes Tumor Growth and Progression via hTERT Signaling and Predicts a Poor Prognosis in Hepatocellular Carcinoma

Liu¹,

Li²,

Lü³

et al. 2017

Theranostics

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Activation of the telomere maintenance mechanism is a key hallmark of cancer. Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, which is highly expressed in more than 80% of tumors, including hepatocellular carcinoma (HCC). However, the exact mechanisms by which hTERT is up-regulated in HCCs and promotes tumor growth and progression is not fully understood. The aim of this study was to discover the novel molecular targets that modulate hTERT signaling and HCC growth. In this study, we pulled down and identified RBFOX3 (RNA binding protein fox-1 homolog 3) as a novel hTERT promoter-binding protein in HCC cells using biotin-streptavidin-agarose pull-down and proteomics approach, and validated it as a regulatory factor for hTERT signaling and tumor growth in HCCs. Knockdown of RBFOX3 suppressed the promoter activity and expression of hTERT and consequently inhibited the growth and progression of HCC cells in vitro and in vivo. The suppression of HCC growth mediated by RBFOX3 knockdown could be rescued by hTERT overexpression. Conversely, exogenous overexpression of RBFOX3 activated the promoter activity and expression of hTERT and promoted the growth and progression of HCC cells. Moreover, we found that RBFOX3 interacted with AP-2β to regulate the expression of hTERT. Furthermore, we demonstrated that RBFOX3 expression was higher in the tumor tissues of HCC patients compared to the corresponding paracancer tissues, and was positively correlated with hTERT expression. Kaplan-Meier analysis showed that the HCC patients with high levels of RBFOX3 and hTERT had poor prognosis. Collectively, our data indicate that RBFOX3 promotes HCC growth and progression and predicts a poor prognosis by activating the hTERT signaling, and suggest that the RBFOX3/hTERT pathway may be a potential therapeutic target for HCC patients.

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Ret finger protein-like 3 promotes tumor cell growth by activating telomerase reverse transcriptase expression in human lung cancer cells

Cited by 12 publications

References 42 publications

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

RFPL3 and CBP synergistically upregulate hTERT activity and promote lung cancer growth

RBFOX3 Promotes Tumor Growth and Progression via hTERT Signaling and Predicts a Poor Prognosis in Hepatocellular Carcinoma

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