CTCF mediates theTERTenhancer–promoter interactions in lung cancer cells: Identification of a novel enhancer region involved in the regulation ofTERTgene

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Abstract

Telomerase activation is a hallmark of cancer. Although the regulation of the telomerase reverse transcriptase catalytic subunit (TERT), the rate-limiting factor for telomerase activity, has been studied intensively it remains incompletely understood. In cells devoid of telomerase activity,TERTis embedded in a region of condensed chromatin and the chromatin remodeling protein CCCTC-binding factor (CTCF) has been implicated in the inhibition ofTERTexpression. The importance ofTERTactivation for cellular immortalization and carcinogenesis is attested by the fact that the gene is expressed in more than 90% of immortal cell lines and tumors and that gain ofTERTis the most frequent amplification event in early stage lung cancer. This study was designed to study the mechanisms of regulation of theTERTgene expression by the CTCF transcription factor in three human lung cancer cell lines, A427, A549 and H838. Depletion of CTCF by siRNA resulted in reducedTERTmRNA levels in two (A427 and A549) of the three cell lines. A novel enhancer element was identified approximately 4.5 kb upstream of theTERTtranscription start site. Chromatin immunoprecipitation experiments revealed recruitment of CTCF to this enhancer element. Chromosome conformation capture experiments demonstrated the presence of CTCF-dependent chromatin loops between this enhancer element and theTERTproximal promoter in A427 and A549 cell lines. In summary, the results show that CTCF plays an important role in maintainingTERTexpression in a subset of human lung cancer cell lines. This role may be due to CTCF-dependent enhancer–promoter interactions.

What's new?

Telomerase activation is a hallmark of cancer cells. Although the regulation of the telomerase reverse transcriptase catalytic subunit (TERT)--the rate-limiting factor for telomerase activity--has been studied intensively, it remains incompletely understood. This study investigated the mechanisms of regulation ofTERTgene expression by the CTCF transcription factor in three human lung cancer cell lines. Depletion of CTCF by siRNA resulted in reducedTERTmRNA levels in two of the cell lines. A novel enhancer element was identified approximately 4.5 kb upstream of theTERTtranscription start site, where CTCF was recruited and mediated interaction with theTERTpromoter.

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