TP53I11 Functions Downstream of Multiple MicroRNAs to Increase ER Calcium Levels and Inhibits Cancer Cell Proliferation.

Cells meticulously regulate free calcium ion (Ca) concentrations, with the endoplasmic reticulum (ER) being crucial for Ca homeostasis. Disruptions in ER Ca balance can contribute to various diseases, including cancer. Although considerable research has focused on the direct mechanisms of ER Ca 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 Ca levels. From these, 10 miRNAs were found to significantly lower basal ER Ca levels. RNA sequencing analysis indicated that these miRNAs downregulate the tumor suppressor tumor protein p53 (TP53)-inducible protein 11 gene (), which is a key regulator of ER Ca levels. Functional assays confirmed that influences ER Ca levels and affects cancer cell proliferation. Additionally, the chemotherapeutic agent doxorubicin (DOX) was shown to upregulate and enhance ER Ca accumulation. These findings elucidate the central role of TP53I11 in miRNA-mediated regulation of ER Ca homeostasis and suggest potential therapeutic strategies targeting ER Ca upregulation for cancer intervention.