Epigenetic regulation of the human ATP2A3 gene promoter in gastric and colon cancer cell lines

Abstract

The knowledge about the role of calcium‐regulated pathways in cancer cell growth and differentiation could be useful for the development of new therapeutic approaches to diminish its mortality. The ATP2A genes encode for SERCA pumps, which modulate cytosolic Ca2+ concentration, regulating various cellular processes including cell growth. ATP2A3 gene transcriptional down‐regulation has been reported in gastric and colon cancer, but there is still a lack of understanding about the epigenetic processes regulating its transcription. In this work, we report that butyrate, trichostatin A, and 5‐azacytidine treatments increase SERCA3 expression, increased apoptosis, and decreased cell viability of the KATO‐III gastric carcinoma cell line. We analyzed the methylation profile of the ATP2A3 gene promoter CpG island, finding clones with methylated status through −280 to −135 promoter region, harboring Sp1 and AP‐2 binding sites, which could have a role in transcriptional repression. Post‐translational modifications of histones show a major role in the ATP2A3 transcriptional regulation, and our results show histones marks linked to transcriptional repression associated with the −262 to −135 region, this repressive context changed to transcriptional permissive through SERCA3 re‐expressing conditions. These results suggest that the nucleotide sequence from −280 to −135 position is an ATP2A3 epigenetic regulatory CpG region in KATO‐III cells. Analyses of online‐databases show a decreased SERCA3 expression in gastric and colon tumors, as well as overall survival results, showed that high SERCA3 expression could serve as a favorable prognostic marker for colon and gastric cancer patients.

Altered SERCA Expression in Breast Cancer

“…Altered SERCA isoform expression and SERCA-specific gene mutations have been documented in various types of cancer, including lung, colon, and leukemia [ 7 , 38 , 39 , 40 , 41 , 42 ]. Progress in SERCA-specific isoform activities and their role in Ca 2+ signaling will enhance the understanding of how dysregulation in SERCA activity plays a role in tumorigenesis.…”

Anti-Cancer Agents in Proliferation and Cell Death: The Calcium Connection

“…Epigenetic silencing of gene ATP2A3, which codes for SERCA3, is down-regulated in gastric and colon tumors. Treatment of KATO-III cells with butyrate, trichostatin A, and 5-azacytidine increased the expression of SERCA3 and was correlated with increased apoptosis and decreased viability [93]. Mitochondrial Ca 2+ -overload is suggested as a key trigger for programmed cell death.…”

Identification of circRNA–miRNA–mRNA networks contributes to explore underlying pathogenesis and therapy strategy of gastric cancer

“…TSA is another kind of typical HDAC inhibitor used mainly in laboratory experiments. TSA is known to induce cell cycle arrest and apoptosis in different cancer cell lines, and its antitumor effect in solid tumors including GC has been illuminated previously [ 54 ]. Astemizole is an old anti-histamine that can target important proteins involved in the cancer progression, namely, ether à-go-go (Eag1) and Eag-related gene potassium channels [ 55 ], thus inhibiting tumor cell proliferation [ 56 ].…”