KLF4 transcription factor positively regulates the transcription of ATP2A3 gene during the differentiation of human colon and gastric cancer cell lines

Abstract

The sarco(endo)plasmic reticulum Ca2+‐ATPase, ATP2A3 gene, is highly expressed in gastrointestinal cells, but is selectively lost in cancer. Previously, was reported that SERCA3 protein is induced when human gastric and colon cancer cells undergo in vitro differentiation. In this work, we induced differentiation of gastric and colon cancer cells in culture, finding increased SERCA3 mRNA expression and increased transcriptional activity of hATP2A3‐gene‐promoter constructs (up to 50‐fold) after induced differentiation, narrowing the responsive elements within ‐ 135 to +142 bp 5’‐region of the human ATP2A3 promoter containing 8 consensus Sp‐factors binding sites, which previously have shown an important role in the transcriptional regulation of the gene. KLF4 transcription factor is decreased in gastric and colon cancer in a similar pattern to that of SERCA3, and both increase after induced differentiation. In EMSA assays, we found that KLF4 binding increases in differentiated cancer cell lines, suggesting that might function as an activator of ATP2A3 expression. In contrast, the results suggest that Sp3 functions as a repressor in tumor cells keeping low SERCA3 expression. By ChIP assays we found that KLF4 binds to the proximal ATP2A3 promoter as part of a co‐activator complex with the histone‐acetyltransferase p300, regulating positively the transcription of ATP2A3. Supported by grant PAPIIT IN213613.