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TCEAL7, a putative tumor suppressor gene, negatively regulates NF-κB pathway

Abstract

We have previously shown that a frequently downregulated gene, transcription elongation factor A-like 7 (TCEAL7), promoted anchorage-independent growth and modulated Myc activity in ovarian surface epithelial cells immortalized with temperature-sensitive large T antigen and human telomerase reverse transcriptase (OSEtsT/hTERT). Analysis of protein/DNA array showed that TCEAL7 downregulation resulted in an approximately twofold increase in nuclear factor (NF)-κB binding to its target DNA sequence. In this study we showed that short hairpin RNA (shRNA)-mediated downregulation of TCEAL7 in two different immortalized OSE cells showed higher NF-κB activity, as determined using reporter and gel-shift assays. Transient transfection of TCEAL7 inhibited the activation of NF-κB in TCEAL7-downregulated clones, IOSE-523 and in other ovarian cancer cell lines (OVCAR8, SKOV3ip and DOV13), suggesting that TCEAL7 negatively regulates NF-κB pathway. Consistent with this observation, TCEAL7-downregulated clones showed higher levels of NF-κB targets, such as pro-proliferative (cyclin-D1 and cMyc), pro-angiogenic (interleukin (IL)-6, IL-8 and vascular endothelial growth factor (VEGF)), inflammatory (intercellular adhesion molecule 1 (ICAM-1) and cyclooxygenase-2 (Cox-2)) and anti-apoptotic (B-cell lymphoma-extra large (Bcl-xl)) genes when compared with vector controls. Inhibition of NF-κB by IκB kinase (IKK) inhibitor (BMS 345541) attenuated cell survival and proliferation of TCEAL-knockdown clones. Although TCEAL7 inhibited p65 transcriptional activity, it did not modulate the cytoplasmic signaling of the NF-κB pathway, by itself or by tumor necrosis factor-α (TNF-α). Chromatin immunoprecipitation (ChIP) assays revealed increased recruitment of p65 and p300 to the promoters of IL-8 and IL-6 in TCEAL7-downregulated clones. Collectively, these results indicate a novel role for TCEAL7 in the negative regulation of NF-κB signaling at the basal level by modulating transcriptional activity of NF-κB on its target gene promoters, potentially providing a novel mechanism by which NF-κB activity may be deregulated in ovarian cancer cells.

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Acknowledgements

This work was supported by Ovarian Cancer Research Fund to RR as a Program of Excellence grant and with funds from Mayo Foundation and Bernard and Edith Waterman Foundation to VS.

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Correspondence to V Shridhar.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Rattan, R., Narita, K., Chien, J. et al. TCEAL7, a putative tumor suppressor gene, negatively regulates NF-κB pathway. Oncogene 29, 1362–1373 (2010). https://doi.org/10.1038/onc.2009.431

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  • DOI: https://doi.org/10.1038/onc.2009.431

Keywords

  • TCEAL7
  • NF-κB
  • ovarian cancer
  • tumor suppressor gene

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