Epigenetic Silencing of CYYR1 Promotes Lung Adenocarcinoma Progression Through TRIM21‐Dependent Regulation of HMMR Stability

Abstract

ABSTRACT Lung adenocarcinoma (LUAD) remains a leading cause of cancer‐related mortality. Integrative multi‐omics and machine‐learning analyses across independent cohorts identified CYYR1 as a frequently downregulated transmembrane protein in LUAD, with low expression associated with poor prognosis and promoter hypermethylation. CYYR1 restoration suppressed LUAD cell proliferation, migration, invasion, tumor growth, and metastasis. Mechanistically, CYYR1 facilitated TRIM21‐dependent ubiquitination and proteasomal degradation of HMMR, thereby reducing CDC20‐associated oncogenic signaling. Biochemical and cellular analyses supported this CYYR1–TRIM21–HMMR regulatory relationship, while a patient‐derived LUAD organoid model provided proof‐of‐concept evidence that CYYR1 restoration inhibited organoid growth and reduced HMMR, CDC20, and Ki67 expression. CYYR1 restoration also increased cisplatin sensitivity. Genistein treatment was associated with CDC20 modulation and enhanced cisplatin response, and cellular thermal shift assays provided evidence consistent with CDC20 engagement, although CDC20 dependence of the Genistein response remains unproven. Collectively, these findings identify CYYR1 as an epigenetically dysregulated tumor‐suppressive factor that regulates HMMR stability through a TRIM21‐dependent mechanism and reveal a potential therapeutic vulnerability in CYYR1‐deficient LUAD.