A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis
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.
Authors
- Laura Andrejka (ORCID: https://orcid.org/0000-0002-2202-5626)
- Paloma Ruiz (ORCID: https://orcid.org/0000-0001-6208-5087)
- Yuning J. Tang (ORCID: https://orcid.org/0009-0006-7037-2901)
- Jess D. Hebert (ORCID: https://orcid.org/0000-0002-8778-5941)
- Deniz Nesli Dolcen (ORCID: https://orcid.org/0000-0003-2441-7313)
- Emily L. Ashkin (ORCID: https://orcid.org/0000-0001-7363-7860)
- Howard Y. Chang (ORCID: https://orcid.org/0000-0002-9459-4393)
- Julia A. Belk (ORCID: https://orcid.org/0000-0003-4724-6158)
- Haiqing Xu (ORCID: https://orcid.org/0000-0002-9124-3192)
- Monte M. Winslow (ORCID: https://orcid.org/0000-0002-5730-9573)
- Hongchen Cai (ORCID: https://orcid.org/0000-0002-5921-5773)
- Jesse R. Dixon (ORCID: https://orcid.org/0000-0002-6273-2181)
- King L. Hung (ORCID: https://orcid.org/0000-0002-3662-4662)
- Dmitri A. Petrov (ORCID: https://orcid.org/0000-0002-3664-9130)
- Rui Li (ORCID: https://orcid.org/0000-0003-0056-7210)
- Steven S. Lopez (ORCID: https://orcid.org/0009-0008-0926-0016)
- Zhichao Xu (ORCID: https://orcid.org/0000-0002-0532-1706)
- Tula Keal (ORCID: https://orcid.org/0009-0007-7760-9315)
Institutions
- Salk Institute for Biological Studies (US)
- Howard Hughes Medical Institute (US)
- Chan Zuckerberg Initiative (United States) (US)
- Stanford University (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2024-10-31
- DOI
- https://doi.org/10.1084/jem.20240765
- Citations
- 1
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.23
Funders
- National Science Foundation
- Howard Hughes Medical Institute
- American Association for Cancer Research
- American Cancer Society
- Tobacco-Related Disease Research Program
- Stanford University
- National Institutes of Health
- Canadian Institutes of Health Research
- National Cancer Institute
- Stanford Cancer Institute