CCDC50 Promotes Tumor Growth Through Regulation of Lysosome Homeostasis

Authors

Penghui Jia
Tian Tian
Zibo Li
Yicheng Wang
Yuxin Lin
Weijie Zeng
Yu Ye
Miao He
Xiangrong Ni
Ji'an Pan
Xiaonan Dong
Jian Huang
Chun-Mei Li
Deyin Guo
Panpan Hou

Publication Date

10-9-2023

Journal

EMBO Reports

Abstract

The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 suppresses tumor growth and lung metastasis, and enhances the effect of BRAFV600E inhibition. Thus, we demonstrate critical roles of CCDC50-mediated clearance of damaged lysosomes in supporting tumor growth, hereby identifying a potential therapeutic target of melanoma.

Keywords

Lysosomes, Humans, Homeostasis, Autophagy, Melanoma, Cell Line, Tumor, Animals, Cell Proliferation, Mice, Ubiquitination, Reactive Oxygen Species, Proto-Oncogene Proteins B-raf, CCDC50, cell death, lysophagy, lysosome damage, melanoma, Autophagy & Cell Death, Cancer, Organelles

Comments

Supplementary Materials

PMID: 37672005