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

作者:Zheng, Shanliang; Zhao, Dong; Hou, Guixue; Zhao, Song; Zhang, Wenxin; Wang, Xingwen; Li, Li; Lin, Liang; Tang, Tie-Shan; Hu, Ying*
来源:PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2022, 119(6): e2111380119.
DOI:10.1073/pnas.2111380119

摘要

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.

  • 单位
    中国科学院研究生院; 哈尔滨医科大学; y; 深圳华大基因研究院