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The Ca -ATPases from the Sarco/endoplasmic reticulum (SERCA) are fundamental for maintaining intracellular [Ca ] homeostasis by pumping Ca into the endoplasmic reticulum (ER) of eukaryotic cells. SERCA enzymes are encoded by three different genes (ATP2A1-3), whose expression occurs in a tissue and development stage-specific manner. It has been reported alterations in the expression of SERCA2 and SERCA3 pumps in different types of cancer: oral, lung, colon, stomach, central nervous system, thyroid, breast, and prostate. Resveratrol (RSV), a phytoalexin produced by a wide variety of plants in response to stress situations can modulate cellular processes involved in all stages of carcinogenesis. In this work, we used breast cancer cell lines (MCF-7 and MDA-MB-231) to evaluate mRNA levels of ATP2A2 and ATP2A3 genes in response to RSV treatment. Our results demonstrate that RSV treatment induced the expression of ATP2A3 gene in both cell lines in a time and concentration-dependent manner, while the expression of ATP2A2 gene remained unaffected. The RSV-induced expression of SERCA3 in these breast cancer cell lines produced decreased cell viability, triggered apoptosis and changes in cytosolic Ca levels, as well as changes in the capacity for Ca release by the ER. These data suggest an important participation of SERCA3 genes in RSV-mediated anti-tumor effect in breast cancer cell lines. Nevertheless, further research is needed to elucidate the molecular mechanisms underlying this effect.

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.

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