A role for candidate tumor-suppressor gene TCEAL7 in the regulation of c-Myc activity, cyclin D1 levels and cellular transformation

Abstract

The pathophysiological mechanisms that drive the development and progression of epithelial ovarian cancer remain obscure. Recently, we identified TCEAL7 as a transcriptional regulatory protein often downregulated in epithelial ovarian cancer. However, the biological significance of such downregulation in cancer is not currently known. Here, we show that TCEAL7 is downregulated frequently in many human cancers and that in immortalized human ovarian epithelial cells this event promotes anchorageindependent cell growth. Mechanistic investigations revealed that TCEAL7 associates with cyclin D1 promoter containing Myc E-box sequence and transcriptionally represses cyclin D1 expression. Moreover, downregulation of TCEAL7 promotes DNA-binding activity of Myc-Max, and upregulates the promoter activity of c-Myc-target gene, ornithine decarboxylase (ODC), whereas enhanced expression of TCEAL7 inhibits Myc-induced promoter activity of ODC. Our findings suggest that TCEAL7 may restrict ovarian epithelial cell transformation by limiting Myc activity. These results also suggest a potential, alternative mechanism by which c-Myc activity may be deregulated in cancer by the downregulation of TCEAL7.

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

“…Immunoblot analysis showed that there was a complete loss of TCEAL7 expression in several clonal lines when compared with vector clones (Chien et al, 2008). shRNA-stable clones (C4-2 and C4-4), which showed significant downregulation of TCEAL7 expression compared with vectortransduced clones (V1 and V3) ( Figure 1a) by real-time PCR, were chosen for further analysis.…”

“…TCEAL7 negatively regulates NF-jB pathway R Rattan et al Our previous analysis of protein/DNA binding assay for 54 transcription factors, using nuclear lysates from OSEtsT/hTERT clonal lines with TCEAL7 (control shRNA vector, V1) or without TCEAL7 (TCEAL shRNA clone, C4-2) (Chien et al, 2008), identified several transcription factors modulated by loss of TCEAL7 including NF-kB, which showed an approximately twofold increase in NF-kB binding to its target sequence in TCEAL7 in C4-2 clone compared with clone V1 (Figure 1b).…”

“…Inhibition of NF-kB pathway reverses the growth potential conferred by TCEAL-7 loss We previously reported that TCEAL7 loss results in increased proliferation in OSEtsT/hTERT cells, and forced expression of TCEAL7 promoted apoptosis in ovarian and cervical cancer cell lines (Chien et al, 2008). We used an IKK inhibitor (BMS345541) to inhibit NF-kB pathway to examine its effect on cell proliferation and survival in TCEAL7-downregulated OSEtsT/ hTERT clones.…”

“…Ectopic expression of TCEAL7 in TCEAL7-non-expressing cell lines induced cell death and suppressed colony-forming abilities (Chien et al, 2005). Recent studies indicate that stable downregulation of TCEAL7 expression in ovarian surface epithelial cells immortalized with temperature-sensitive large T antigen and human telomerase reverse transcriptase (OSEtsT/ hTERT) cells confers increased proliferation potential and an ability to form soft-agar colonies and results in upregulation of Myc activity (Chien et al, 2008). These findings suggest that loss of TCEAL7 expression may promote the survival and growth of ovarian cancer cells.…”

“…In an effort to identify transcription factors modulated by TCEAL7 loss, we previously analyzed the DNA-binding activity of 54 transcriptional factors using the protein/DNA array (TranSignal Array I, Panomics, Fremont, CA, USA) in clonal line without TCEAL7 (TCEAL7 short hairpin RNA (shRNA)) compared with the clonal line with TCEAL7 (control shRNA) expression (Chien et al, 2008). Among the 54 transcription factors tested, we identified nuclear factor (NF)-kB as one of the transcription factors whose DNA-binding activity was modulated by TCEAL7 downregulation.…”