Abstract
Cells meticulously regulate free calcium ion (Ca2+) concentrations, with the endoplasmic reticulum (ER) being crucial for Ca2+ homeostasis. Disruptions in ER Ca2+ balance can contribute to various diseases, including cancer. Although considerable research has focused on the direct mechanisms of ER Ca2+ regulation, the role of microRNAs (miRNAs) in this process remains underexplored. Mainly using data from a CRISPR-based genomic screening previously conducted in our laboratory, we identified 33 candidate miRNAs that may regulate ER Ca2+ levels. From these, 10 miRNAs were found to significantly lower basal ER Ca2+ levels. RNA sequencing analysis indicated that these miRNAs downregulate the tumor suppressor tumor protein p53 (TP53)-inducible protein 11 gene (TP53I11), which is a key regulator of ER Ca2+ levels. Functional assays confirmed that TP53I11 influences ER Ca2+ levels and affects cancer cell proliferation. Additionally, the chemotherapeutic agent doxorubicin (DOX) was shown to upregulate TP53I11 and enhance ER Ca2+ accumulation. These findings elucidate the central role of TP53I11 in miRNA-mediated regulation of ER Ca2+ homeostasis and suggest potential therapeutic strategies targeting ER Ca2+ upregulation for cancer intervention.