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

Abstract

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.

Blood transcriptional and microRNA responses to short-term exposure to disinfection by-products in a swimming pool

“…CREBBP, a gene involved in the transcriptional co-activation of a large variety of transcription factors, was found to have genetic aberrations in individuals with bladder cancer (Gui et al, 2011). According to the literature, CREBBP up-regulates hTERT activity, promoting lung cancer growth (Qin et al, 2015). In our study we found a positive association between CREBBP and all DBP exposures (range of regression coefficients 0.05-6.37).…”

KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway

“… 61 Multiple transcription factor binding sites exist in the promoter region of hTERT, and its expression is tightly controlled by transcriptional activactors 62 , 63 and tumor suppressors. 35 Besides, methylation of the histones at the hTERT promoter region recruits histone acetyl transferase and promotes hTERT transcription. 64 Nonetheless, it remains unclear how hTERT is regulated in melanoma.…”

“… 30 , 31 Overexpression of hTERT is a common feature of most human cancers believed to support cell immortalization. 32 , 33 , 34 So far, it is known that hTERT is modulated at genetic, mRNA, protein and subcellular localization levels, 31 and transcription factors including c-Myc, NF- κ B, STAT proteins and estrogen receptors 35 have been reported to bind to the hTERT promoter to modulate its expression. The highly recurrent mutations in the promoter of TERT are found in over 50 cancer types, including papillary thyroid carcinoma, 36 , 37 hepatocellular carcinoma, 38 epithelioid glioblastoma, 39 bladder cancer, 40 malignant pleural mesothelioma, 41 melanoma, 42 , 43 , 44 , 45 are the most common mutation in many cancers.…”

β-Catenin Cooperates with CREB Binding Protein to Promote the Growth of Tumor Cells

“…Based on the previous studies showing that CBP not only regulated lung carcinoma growth by activating multiple signaling pathways [16], but also interacted with β-catenin as a transcriptional co-activator to activate downstream target genes [17], we deduced that they might synergize to co-regulate lung tumor growth. To test this hypothesis, immunofluoresence assay was performed.…”