SOD1 regulates ribosome biogenesis in KRAS mutant non-small cell lung cancer

Abstract

SOD1 is known as the major cytoplasmic superoxide dismutase and an anticancer target. However, the role of SOD1 in cancer is not fully understood. Herein we describe the generation of an inducible Sod1 knockout in KRAS-driven NSCLC mouse model. Sod1 knockout markedly reduces tumor burden in vivo and blocks growth of KRAS mutant NSCLC cells in vitro. Intriguingly, SOD1 is enriched in the nucleus and notably in the nucleolus of NSCLC cells. The nuclear and nucleolar, not cytoplasmic, form of SOD1 is essential for lung cancer cell proliferation. Moreover, SOD1 interacts with PeBoW complex and controls its assembly necessary for pre-60S ribosomal subunit maturation. Mechanistically, SOD1 regulates co-localization of PeBoW with and processing of pre-rRNA, and maturation of cytoplasmic 60S ribosomal subunits in KRAS mutant lung cancer cells. Collectively, our study unravels a nuclear SOD1 function essential for ribosome biogenesis and proliferation in KRAS-driven lung cancer.

Identifying Lung Cancer Cell Markers with Machine Learning Methods and Single-Cell RNA-Seq Data

“…Other biological process terms may also be linked to the tumorigenesis of lung cancer in their respective ways. For the cellular component cytosolic small ribosomal subunit, it has been shown to be abnormally regulated during the initiation and metastasis of lung cancer [ 114 ], corresponding with our results. As for the structural constituent of ribosome, in the same paper [ 114 ], authors also validated the specific role of ribosome during lung cancer tumorigenesis.…”

Effects of Hydrogen Peroxide Stress on the Nucleolar Redox Environment and Pre-rRNA Maturation

“…One biologically important ROS type in both homeostatic and stress situations is superoxide (Imlay, 2008), detoxified in part by superoxide dismutases (SODs). We have recently found that a fraction of mouse SOD1 localizes to the nucleolus and facilitates the generation of 60S ribosomal subunits in lung cancer cells (Wang et al, 2021). Thus, it appears that protecting pre-rRNA and the ribosome-building pathway from oxidative damage requires synergistic activities of different types of antioxidant mechanisms.…”

Nuclear SOD1 in Growth Control, Oxidative Stress Response, Amyotrophic Lateral Sclerosis, and Cancer

“…In inducible erbB2 (MMTV-iErbB2) and Wnt (MMTV-Wnt) transgene breast cancer models in mice, Sod1 knockout attenuates these oncogene-driven proliferations, but not normal proliferation of the mammary gland associated with pregnancy or other normal proliferative tissues, such as skin and gastro-intestinal tract epithelium [ 16 ]. Similarly, in a Kras/TP53 lung tumor-initiation model, tamoxifen-inducible Sod1 knockout significantly reduced lung tumor burdens due to inhibition of cancer cell proliferation [ 21 ]. In contrast, Sod1 knockout does not have discernible effect on proliferation of normal lung cells or other tissues [ 21 ].…”

“…Similarly, in a Kras/TP53 lung tumor-initiation model, tamoxifen-inducible Sod1 knockout significantly reduced lung tumor burdens due to inhibition of cancer cell proliferation [ 21 ]. In contrast, Sod1 knockout does not have discernible effect on proliferation of normal lung cells or other tissues [ 21 ]. These observations document that SOD1 is an oncogene.…”