HRP2 regulating MICU1-mediated Ca2+ overload to dictate chemoresistance of multiple myeloma

Despite the efficacy of bortezomib (BTZ)-based chemotherapy in treating multiple myeloma (MM) patients, chemoresistance occurs frequently over time, particularly in individuals exhibiting an initial positive response to BTZ therapy. In this study, we established BTZ-resistant MM cells and identified that suppressed expression of the hepatoma-derived growth factor (HDGF)-related protein-2 (HRP2) was a key determinant of chemoresistance in MM cells. Manipulating HRP2 expression remodeled the chemosensitivity of MM cells in vitro and in vivo. Clinically, lower expression of HRP2 predicted a shorter survival rate in MM patients receiving BTZ-based regimens. Mechanistically, HRP2 depletion resulted in elevated acetylation modifications of histone 3 at lysine 27 (H3K27Ac), and enhanced chromatin accessibility as well as transcriptional elongation of mitochondrial calcium uptake 1(MICU1) gene, thus promoting the expression of MICU1 gene and alleviating calcium (Ca²⁺) overload and excessive reactive oxygen species (ROS) induced mitochondria damage and apoptosis in MM cells. Thereby, MICU1 suppression improved BTZ sensitivity in vitro and relieved tumor burden in a mouse model of MM. Similarly, elevated MICU1 expression was observed in the B220⁺CD19⁺ B cells from HRP2-knockout mice and significantly correlated with poor prognosis in the clinic. Thus, our study elucidates the previously unrecognized epigenetic role of HRP2 in regulating calcium homeostasis of MM cells, providing new theoretical insights into the mechanisms underlying the development of drug resistance in multiple myeloma.