Binding of transcription factors to mutated DNA sequences is a likely regulator of cancer progression. Noncoding regulatory mutations such as those on the core promoter of the gene encoding human telomerase reverse transcriptase have been shown to affect gene expression in cancer. Using a protein microarray of 667 transcription factor DNA-binding domains and subsequent functional assays, we looked for transcription factors that preferentially bind the mutant hTERT promoter and characterized their downstream effects. One of them, friend leukemia integration 1 (FLI1), which belongs to the E26 transforming-specific family of transcription factors, exhibited particularly strong effects with respect to regulating hTERT expression, while the even better binding ELK3 did not. Depletion of FLI1 decreased expression of the genes for cyclin D1 (CCND1) and E2F transcription factor 2 (E2F2) resulting in a G1/S cell cycle arrest and in consequence a reduction of cell proliferation. FLI1 also affected CMTM7, another gene involved in G1/S transition, although by another process that suggests a balanced regulation of the tumor suppressor gene's activity via opposing regulation processes. FLI1 expression was found upregulated and correlated with an increase in CCND1 expression in pancreatic cancer and brain tumors. In non-neoplastic lung cells, however, FLI1 depletion led to rapid progression through the cell cycle. This coincides with the fact that FLI1 is downregulated in lung tumors. Taken together, our data indicate a cell cycle regulatory hub involving FLI1, hTERT, CCND1 and E2F2 in a tissue- and context-dependent manner.

中文翻译：

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转录因子FLI1通过影响细胞周期调控来促进癌症进展。

转录因子与突变的DNA序列的结合可能是癌症进展的调节因子。非编码调节突变，例如编码人端粒酶逆转录酶的基因的核心启动子上的突变，已显示会影响癌症中的基因表达。使用具有667个转录因子DNA结合域的蛋白质微阵列和后续功能分析，我们寻找了优先结合突变hTERT启动子的转录因子，并表征了其下游效应。其中之一，属于E26转化特异性转录因子家族的友人白血病整合1（FLI1），在调节hTERT表达方面表现出特别强的作用，而结合得更好的ELK3则没有。FLI1的耗竭会降低细胞周期蛋白D1（CCND1）和E2F转录因子2（E2F2）的基因表达，从而导致G1 / S细胞周期停滞并因此降低细胞增殖。FLI1还影响了CMTM7，CMTM7是另一个参与G1 / S过渡的基因，尽管通过另一个过程表明，通过相反的调控过程可以平衡调节抑癌基因的活性。发现FLI1表达上调并且与胰腺癌和脑肿瘤中CCND1表达的增加相关。然而，在非肿瘤性肺细胞中，FLI1耗竭导致整个细胞周期快速进展。这与FLI1在肺肿瘤中下调的事实相吻合。综上所述，我们的数据表明，涉及FLI1，hTERT，