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Background  Multiple myeloma (MM) cell motility is a critical step during MM dissemination throughout the body, but how it is regulated remains largely unknown. As hypercalcemia is an important clinical feature of MM, high calcium (Ca 2+ ) and altered Ca 2+  signaling could be a key contributing factor to the pathological process.    Methods  Bioinformatics analyses were employed to assess the clinical significance of Ca 2+  influx channels in clinical specimens of smoldering and symptomatic MM. Functional and regulatory roles of influx channels and downstream signaling in MM cell migration and invasion were conducted and experimental MM dissemination was examined in a xenograft mouse model using in vivo live imaging and engraftment analysis.    Results  Inhibition of TRPM7, ORAI1, and STIM1 influx channels, which are highly expressed in MM patients, and subsequent blockage of Ca 2+  influx by CRISPR/Cas9 and small molecule inhibitors, effectively inhibit MM cell migration and invasion, and attenuate the experimental MM dissemination. Mechanistic studies reveal a nutrient sensor  O -GlcNAcylation as a downstream regulator of Ca 2+  influx that specifically targets cell adhesion molecules. Hyper -O -GlcNAcylation following the inhibition of Ca 2+  influx channels induces integrin α4 and integrin β7 downregulation via ubiquitin-proteasomal degradation and represses the aggressive MM phenotype.    Conclusions  Our findings unveil a novel regulatory mechanism of MM cell motility via Ca 2+  influx/ O -GlcNAcylation axis that directly targets integrin α4 and integrin β7, providing mechanistic insights into the pathogenesis and progression of MM and demonstrating potential predictive biomarkers and therapeutic targets for advanced MM.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13046-021-01876-z.

O-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination