Sp1 upregulates expression of TRF2 and TRF2 inhibition reduces tumorigenesis in human colorectal carcinoma cells

Abstract

Telomeres are essential for the maintenance of genomic integrality, they enable

complete DNA replication, organize subnuclear domains, and protect chromosome ends

against fusion. Loss of telomere function in human cells results in the formation of

dicentric chromosomes and other abnormalities such as end-to-end fusions.TRF2 is a

ubiquitously expressed protein which binds directly to the tandem array of duplex

telomeric repeats and is involved in the telomere structure and chromosome end

protection. Inhibition of TRF2 induces end-to-end chromosome fusions and growth arrest

or apoptosis in human melanoma cells.Lack of TRF2 in ALT cells also caused PMLdependent

p53 activation and loss of telomeric DNA.TRF2 over-expression is found in

several human tumors such as breast carcinomas, liver hepatocarcinomas, lung

carcinomas and gastric carcinomas. This suggests that TRF2 may have a role in

tumorigenisis.Cancers of the gastrointestinal tract share numerous common genetic

features despite differing widely in incidence and outcome.However, the role and

mechanisms that lead to over-expressed TRF2 in colorectal carcinoma are not well

known. Sp1 is a member of the multigene family with sequence-specific DNA-binding

C-terminal zinc-finger motifs, which plays a critical role in the regulation of expression

of mammalian genes lacking a TATA box, by binding to GC/GT boxes to activate

transcription.Cancer-related Sp1 targets include PDEGF, p21, VEGF, TGF-β, cyclin

D1, E2F1, c-fos, transforming growth factor α and osteopontin (OPN).The promoter

of TRF2 is GC-rich sequence (70-75%), which lacks an obvious TATA box. It is unclear

whether or not TRF2 is regulated via Sp1, which may in turn be regulated to genomic

stability. We tested the expression of TRF2 in colorectal carcinoma tissues and colon

carcinoma SW480 cell line, and studied the role of Sp1 in regulating TRF2 expression in

colon carcinoma. Results showed that TRF2 was over-expressed in colorectal carcinoma

tissues and SW480 cell line. It was also shown that Sp1 transcription factor is involved in

the up-regulation of TRF2 expression.