A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis

• Published in: bioRxiv
• Main Authors: Ashkin, Emily L, Tang, Yuning J, Xu, Haiqing, Hung, King L, Belk, Julia, Cai, Hongchen, Lopez, Steven, Dolcen, Deniz Nesli, Hebert, Jess D, Li, Rui, Ruiz, Paloma A, Keal, Tula, Andrejka, Laura, Chang, Howard Y, Petrov, Dmitri A, Dixon, Jesse R, Xu, Zhichao, Winslow, Monte M
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory 19.09.2024
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.09.14.613043

The cohesin complex is a critical regulator of gene expression. 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 show that STAG2 is uniquely tumor suppressive among all core and auxiliary cohesin components. The heterodimeric complex components and have highly correlated effects with in human lung cancer cell lines, are tumor suppressors , and are epistatic to in oncogenic KRAS-driven lung tumorigenesis . STAG2 inactivation elicits changes in gene expression, chromatin accessibility and 3D genome conformation that impact cancer cell state. Gene expression and chromatin accessibility similarities between STAG2- and PAXIP1-deficient neoplastic cells further relates 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. STAG2 is a frequently mutated cohesin subunit across several cancers and one of the most important functional suppressors of lung adenocarcinoma. Our findings underscore important roles of STAG2 in suppressing lung tumorigenesis and highlight a STAG2-PAXIP1/PAGR1 tumor-suppressive program that may transcend cancer type.