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

• Published in: Molecular carcinogenesis Vol. 58; no. 6; pp. 887 - 897
• Main Authors: Meneses‐Morales, Iván, Izquierdo‐Torres, Eduardo, Flores‐Peredo, Lucía, Rodríguez, Gabriela, Hernández‐Oliveras, Andrés, Zarain‐Herzberg, Ángel
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.06.2019
• Subjects: Apoptosis; Azacytidine; Binding Sites; butyrate; Ca2+-transporting ATPase; Calcium; calcium ATPase; Calcium ions; cancer biology; Cell growth; Cell Line, Tumor; Cell viability; Colon cancer; Colonic Neoplasms - genetics; Colorectal cancer; CpG Islands; CpG methylation; DNA Methylation; Down-Regulation; Epigenesis, Genetic; epigenetic regulation; Epigenetics; Gastric cancer; gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Gene silencing; Histones; Histones - metabolism; Humans; Nucleotide sequence; Promoter Regions, Genetic; Regulatory sequences; Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; SERCA3; Sp1 protein; Sp1 Transcription Factor - metabolism; Stomach Neoplasms - genetics; Survival Analysis; transcriptional regulation; Trichostatin A; Tumor cell lines; Tumors; CpG methylation; SERCA3; calcium ATPase; butyrate; transcriptional regulation; cancer biology; epigenetic regulation; gene expression
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.22978

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.