Cytoglobin promotes sensitivity to ferroptosis by regulating p53‐YAP1 axis in colon cancer cells

Abstract

Ferroptosis is an iron‐dependent mode of non‐apoptotic cell death characterized by accumulation of lipid reactive oxygen species (ROS). As a regulator of ROS, cytoglobin (CYGB) plays an important role in oxygen homeostasis and acts as a tumour suppressor. However, the mechanism by which CYGB regulates cell death is largely unknown. Here, we show that CYGB overexpression increased ROS accumulation and disrupted mitochondrial function as determined by the oxygen consumption rate and membrane potential. Importantly, ferroptotic features with accumulated lipid ROS and malondialdehyde were observed in CYGB‐overexpressing colorectal cancer cells. Moreover, CYGB significantly increased the sensitivity of cancer cells to RSL3‐ and erastin‐induced ferroptotic cell death. Mechanically, both YAP1 and p53 were significantly increased based on the RNA sequencing. The knock‐down of YAP1 alleviated production of lipid ROS and sensitivity to ferroptosis in CYGB overexpressed cells. Furthermore, YAP1 was identified to be inhibited by p53 knock‐down. Finally, high expression level of CYGB had the close correlation with key genes YAP1 and ACSL4 in ferroptosis pathway in colon cancer based on analysis from TCGA data. Collectively, our results demonstrated a novel tumour suppressor role of CYGB through p53‐YAP1 axis in regulating ferroptosis and suggested a potential therapeutic approach for colon cancer.

Gene Regulation Network of Prognostic Biomarker YAP1 in Human Cancers: An Integrated Bioinformatics Study

“…Cancer cells exhibit an altered redox status and metabolism, which are associated with mitochondria as they are the major sites of ROS generation and energy metabolism [ 22 ]. Yes-associated protein (YAP) is a transcriptional coactivator that is involved in mitochondrial regulation, such as promoting mitochondrial biogenesis in endothelial cells [ 23 ], to up-regulate the mitochondrial iron exporter genes in yeast [ 24 ], to regulate the mitochondrial respiratory function in rectal and colon cancer cells [ 25 , 26 ]. Despite the intensive observation, the YAP1-mediated mitochondrial dysfunction in human cancers is still elusive.…”

Ferroptosis: A Double-Edged Sword in Gastrointestinal Disease

“…Cytoglobin (CYGB) is a cellular ROS regulator that regulates oxygen homeostasis and acts as a tumor suppressor [109]. Recently, CYGB was reported to regulate ferroptosis through p53-(Yes-associated protein 1) YAP1 signaling in CRC cells [110]. HO-1 increases available cellular iron, which can trigger ferroptosis [46].…”

Blockade of GCH1/BH4 Axis Activates Ferritinophagy to Mitigate the Resistance of Colorectal Cancer to Erastin-Induced Ferroptosis

“…Erastin and RSL3 trigger cell ferroptosis by blocking GPX4-mediated antioxidation ( Yang and Stockwell, 2008 ; Xie et al, 2016 ; Yang and Stockwell, 2016 ; Stockwell et al, 2017 ). Currently, most studies have focused on the canonical GPX4 redox system ( Xia et al, 2020 ; Wang et al, 2021a ; Wang et al, 2021b ; Ye et al, 2021 ). For example, serine and arginine-rich splicing factor 9 (SFRS9) was found as a target to improve CRC cell response to erastin through the regulation of GPX4 ( Wang et al, 2021a ).…”