TY - JOUR
T1 - Chromosomal 3q amplicon encodes essential regulators of secretory vesicles that drive secretory addiction in cancer
AU - Tan, Xiaochao
AU - Wang, Shike
AU - Xiao, Guan Yu
AU - Wu, Chao
AU - Liu, Xin
AU - Zhou, Biyao
AU - Jiang, Yu
AU - Duose, Dzifa Y.
AU - Xi, Yuanxin
AU - Wang, Jing
AU - Gupta, Kunika
AU - Pataer, Apar
AU - Roth, Jack A.
AU - Kim, Michael P.
AU - Chen, Fengju
AU - Creighton, Chad J.
AU - Russell, William K.
AU - Kurie, Jonathan M.
N1 - Publisher Copyright:
© 2024 American Society for Clinical Investigation. All rights reserved.
PY - 2024/6/17
Y1 - 2024/6/17
N2 - Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identified a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase secretory pathway Ca2+ transporting 1 (ATP2C1). We show that GOLIM4 recruited ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate Ca2+-dependent cargo loading, Golgi membrane bending, and vesicle scission. GOLIM4 depletion disrupted the protein complex, resulting in a secretory blockade that inhibited the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintained intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiated the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibited the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupted prosurvival autocrine loops and attenuated prometastatic processes in the tumor microenvironment. As it potentially underlies the selective activity of Mn against 3q-amplified malignancies, ATP2C1 coamplification increased Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between coamplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.
AB - Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identified a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase secretory pathway Ca2+ transporting 1 (ATP2C1). We show that GOLIM4 recruited ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate Ca2+-dependent cargo loading, Golgi membrane bending, and vesicle scission. GOLIM4 depletion disrupted the protein complex, resulting in a secretory blockade that inhibited the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintained intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiated the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibited the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupted prosurvival autocrine loops and attenuated prometastatic processes in the tumor microenvironment. As it potentially underlies the selective activity of Mn against 3q-amplified malignancies, ATP2C1 coamplification increased Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between coamplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.
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U2 - 10.1172/JCI176355
DO - 10.1172/JCI176355
M3 - Article
C2 - 38662435
AN - SCOPUS:85196810641
SN - 0021-9738
VL - 134
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
M1 - e176355
ER -