SOD1 Promotes Cell Proliferation and Metastasis in Non-small Cell Lung Cancer via an miR-409-3p/SOD1/SETDB1 Epigenetic Regulatory Feedforward Loop

Abstract

Superoxide dismutase 1(SOD1) is a major antioxidant with oncogenic effects in many human cancers. Although SOD1 is overexpressed in various cancers, the clinical significance and functions of SOD1 in non-small cell lung cancer (NSCLC), particularly the epigenetic regulation of SOD1 in NSCLC carcinogenesis and progression have been less well investigated. In this study, we found that SOD1 expression was upregulated in NSCLC cell lines and tissues. Further, elevated SOD1 expression could promote NSCLC cell proliferation, invasion and migration. While inhibition of SOD1 expression induced NSCLC G1-phase cell cycle arrest and promoted apoptosis. In addition, miR-409-3p could repress SOD1 expression and significantly counteract its oncogenic activities. Bioinformatics analysis indicated that SET domain bifurcated histone lysine methyltransferase1 (SETDB1) was involved in the epigenetic regulation of miR-409-3p and SOD1 expression and functions in NSCLC cells. Identification of this miR-409-3p/SOD1/SETDB1 epigenetic regulatory feedforward loop may provide new insights into further understanding of NSCLC tumorigenesis and progression. Additionally, our results incicate that SOD1 may be a potential new therapeutic target for NSCLC treatment.

Exosome-mediated radiosensitizing effect on neighboring cancer cells via increase in intracellular levels of reactive oxygen species

“…SOD1, which is overexpressed in several types of cancer cell, such as breast ( 42 ) and non-small lung cancer cells ( 43 ) may be essential for the maintenance of cellular ROS levels. Papa et al ( 44 ) reported that SOD1 serves an important role in cancer progression and described a potential association between SOD1 overexpression and regulation of the mitochondrial unfolded-protein response.…”

Visceral Adipose Tissue of Prediabetic and Diabetic Females Shares a Set of Similarly Upregulated microRNAs Functionally Annotated to Inflammation, Oxidative Stress and Insulin Signaling

“…Thus, miR-409-3p may be transiently changed in response to increased blood glucose levels in VAT. Its role may be connected with regulation of insulin signaling (Akt1, Pdk1) and antioxidant defense genes (e.g., Sod1) [ 59 , 60 , 61 ]. Considering inflammation, miR-409-3p was confirmed to increase production of inflammatory cytokines via regulating SOCS3/STAT3 pathway [ 62 ].…”

Chebulinic acid inhibits MDA‐MB‐231 breast cancer metastasis and promotes cell death through down regulation of SOD1 and induction of autophagy

“…As such SOD1 is a pro survival factor and has been shown to be up regulated in cancers. Inhibition of SOD1 activity enhances cell death and apoptosis in cancer cells (Gomez, Shah et al, 2019; Liu et al, 2020). Therefore, targeting SOD1 might of therapeutic importance in cancers.…”

“…SOD1 is mainly localized to the cytoplasm but is also found in the mitochondrial intermembrane space and nucleus (Tsang, Liu, Thomas, Zhang, & Zheng, 2014). SOD1 functions as an antioxidant, and can provide protection from cell death to cancer cells (Banks and Andersen, 2019; Liu et al, 2020). Importantly, SOD1 has been shown to be up regulated in many cancer types and is being evaluated as a novel target in cancer therapy (Papa, Manfredi, & Germain, 2014).…”

“…Also inhibition of SOD1 has been shown to induce apoptosis in cancer cells (Li et al, 2019). Beside, elevated levels of SOD1 have also been observed in breast cancer and lung cancer patients (Gomez, Shah, Kenny, Jenkins, & Germain, 2019; Liu et al, 2020).…”