KRM2 promotes renal cell carcinoma progression and inhibits ferroptosis by interacting with ATF2

Abstract

The role of kringle-containing transmembrane protein 2 (KRM2) in renal cell carcinoma (RCC) remains unknown. This study aimed to explore KRM2's mechanistic role in regulating RCC progression. Tissue microarrays were used to map KRM2 expression in tumor tissues and analyze its relationship with RCC clinical features. Cell models were constructed by transfecting RCC cell lines with KRM2 knockdown, KRM2 overexpression, or ATF2 knockdown lentiviral vectors. Tumor xenografts were generated in nude mice to observe the effects of KRM2 on tumor formation. A gene expression microarray was used to identify the regulatory genes downstream of KRM2 and their binding relationships were verified by co-immunoprecipitation and cycloheximide pulse-chase assay. Through a series of in vitro experiments, effects of altering KRM2 and ATF2 expression on cell function and ferroptosis indicators were observed. Following these, we found that KRM2 expression significantly increased in RCC tumor tissues and was associated with tumor size, grade, stage, infiltration, and patient age. In vivo experiments confirmed that inhibition of KRM2 expression slowed the tumor growth. Silencing of KRM2 in RCC cells also significantly inhibited cell proliferation and migration and facilitated apoptosis and ferroptosis. ATF2 is predicted to be downstream of KRM2. Its expression is positively regulated by KRM2 and there was targeted binding between proteins. In vitro experiments further suggested that ATF2 knockdown reversed the cancer-promoting and ferroptosis-inhibiting effects of KRM2 in RCC. In conclusion, KRM2 plays an oncogenic role in RCC by promoting tumor progression and ferroptosis via regulation of its downstream target, ATF2.