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

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 (<i>TP53I11</i>), which is a key regulator of ER Ca²⁺ levels. Functional assays confirmed that <i>TP53I11</i> influences ER Ca²⁺ levels and affects cancer cell proliferation. Additionally, the chemotherapeutic agent doxorubicin (DOX) was shown to upregulate <i>TP53I11</i> 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.