1. A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis.
- Author
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Ashkin EL, Tang YJ, Xu H, Hung KL, Belk JA, Cai H, Lopez SS, Dolcen DN, Hebert JD, Li R, Ruiz PA, Keal T, Andrejka L, Chang HY, Petrov DA, Dixon JR, Xu Z, and Winslow MM
- Subjects
- Humans, Animals, Cell Line, Tumor, Mice, Gene Expression Regulation, Neoplastic, CRISPR-Cas Systems, Antigens, Nuclear metabolism, Antigens, Nuclear genetics, Tumor Suppressor Proteins metabolism, Tumor Suppressor Proteins genetics, Cohesins, Lung Neoplasms pathology, Lung Neoplasms metabolism, Lung Neoplasms genetics, Cell Cycle Proteins metabolism, Cell Cycle Proteins genetics, Carcinogenesis genetics, Carcinogenesis metabolism
- Abstract
The cohesin complex is a critical regulator of gene expression. STAG2 is the most frequently mutated cohesin subunit across several cancer types and is a key tumor suppressor in lung cancer. Here, we coupled somatic CRISPR-Cas9 genome editing and tumor barcoding with an autochthonous oncogenic KRAS-driven lung cancer model and showed that STAG2 is uniquely tumor-suppressive among all core and auxiliary cohesin components. The heterodimeric complex components PAXIP1 and PAGR1 have highly correlated effects with STAG2 in human lung cancer cell lines, are tumor suppressors in vivo, and are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo. STAG2 inactivation elicits changes in gene expression, chromatin accessibility, and 3D genome conformation that impact the cancer cell state. Gene expression and chromatin accessibility similarities between STAG2- and PAXIP1-deficient neoplastic cells further relate STAG2-cohesin to PAXIP1/PAGR1. These findings reveal a STAG2-PAXIP1/PAGR1 tumor-suppressive axis and uncover novel PAXIP1-dependent and PAXIP1-independent STAG2-cohesin-mediated mechanisms of lung tumor suppression., (© 2024 Ashkin et al.)
- Published
- 2025
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