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

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Abstract

hTERT is the key component of telomerase and its overactivation contributesto maintaining telomere length and cell immortalization. Previously, we identified RFPL3 as a new transcription activator of hTERT in lung cancers. However, theexact mechanism of RFPL3 in mediating hTERT activation and its associated signalregulatory network remain unclear. In this study, we found that RFPL3 colocalized andinteracted directly with CBP in the nucleus of lung cancer cells. Immunohistochemicalanalysis of tissue microarrays of lung cancers revealed the simultaneousoverexpression of both RFPL3 and CBP predicted relatively poor prognosis. Furthermore, we confirmed their synergistic stimulation on hTERT expression andtumor cell growth. The binding of RFPL3 to hTERT promoter was reduced markedlywhen CBP was knocked down by its specific siRNA or suppressed by its inhibitor inlung cancer cells with stable overexpression of RFPL3. When one of the two proteins RFPL3 and CBP was upregulated or downregulated, whereas the another remainsunchanged, hTERT expression and telomerase activity were activated or repressedaccordingly. In the meantime, the growth of lung cancer cells was also promoted orattenuated accordingly. Furthermore, we also found that RFPL3 coordinated withCBP to upregulate hTERT through the CBP-induced acetylation of RFPL3 protein andtheir co-anchoring at hTERT promoter region. Collectively, our results reveal a newmechanism 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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Qin, Y., Chen, W., Xiao, Y., Yu, W., Cai, X., Dai, M., … Wu, T. (2015). RFPL3 and CBP synergistically upregulate hTERT activity and promote lung cancer growth. Oncotarget, 6(29), 27130–27145. https://doi.org/10.18632/oncotarget.4825

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