iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca²⁺ homeostasis and control tumor growth and drug resistance.

Abstract

Ca²⁺ release from the endoplasmic reticulum (ER) is an essential event in the modulation of Ca²⁺ homeostasis, which is coordinated by multiple biological processes, ranging from cell proliferation to apoptosis. Deregulated Ca²⁺ homeostasis is linked with various cancer hallmarks; thus, uncovering the mechanisms underlying Ca²⁺ homeostasis dynamics may lead to new anticancer treatment strategies. Here, we demonstrate that a reported Ca²⁺-channel protein TMCO1 (transmembrane and coiled-coil domains 1) is overexpressed in colon cancer tissues at protein levels but not at messenger RNA levels in colon cancer. Further study revealed that TMCO1 is a substrate of ER-associated degradation E3 ligase Gp78. Intriguingly, Gp78-mediated TMCO1 degradation at K186 is under the control of the iASPP (inhibitor of apoptosis-stimulating protein of p53) oncogene. Mechanistically, iASPP robustly reduces ER Ca²⁺ stores, mainly by competitively binding with Gp78 and interfering with Gp78-mediated TMCO1 degradation. A positive correlation between iASPP and TMCO1 proteins is further validated in human colon tissues. Inhibition of iASPP-TMCO1 axis promotes cytosolic Ca²⁺ overload-induced apoptotic cell death, reducing tumor growth both in vitro and in vivo. Thus, iASPP-TMCO1 represents a promising anticancer treatment target by modulating Ca²⁺ homeostasis.