Epigenetic regulation of Cereblon in cancer: molecular mechanisms and clinical implications.

BACKGROUND

Cereblon (CRBN) serves as the substrate recognition subunit of the CRL4-CRBN E3 ubiquitin ligase complex and isthe primary target of immunomodulatory drugs (IMiDs) in cancer therapy. While CRBN mutations occur infrequently in cancer, reduced CRBN expression correlates with poor IMiD response and treatment resistance, suggesting nongeneticregulatory mechanisms may govern CRBN expression.

OBJECTIVE

We investigated CRBN expression patterns across multiple cancer types and examined the role of promotermethylation in regulating CRBN expression and its clinical significance.

METHODS

We analyzed CRBN expression patterns using GENT2 database analysis and examined CRBN methylation status indiverse human cancer cell lines using methylation-specific PCR (MSP) and bisulfite genomic sequencing. We analyzedthe clinical significance of CRBN methylation and expression using TCGA and GENT2 databases with Kaplan-Meiersurvival analyses.

RESULTS

CRBN expression was significantly downregulated in breast, cervical, head and neck, lung, and skin cancers comparedto normal tissues. We identified a CpG island 1kb upstream of the CRBN transcriptional start site, with cancer celllines exhibiting partial methylation patterns. Bisulfite sequencing confirmed specific CpG methylation sites withinCRBN promoter regions. CRBN promoter hypermethylation significantly correlated with increased mortality risk inbreast, lung, acute myeloid leukemia, and bladder cancers, while low CRBN expression was associated with poorsurvival in breast, lung, brain, and ovarian cancers. Combined low expression and high methylation stronglypredicted poor outcomes in breast and lung cancers.

CONCLUSIONS

CRBN expression is partially regulated by promoter methylation in specific cancer types, with epigenetic silencingcontributing to treatment resistance and poor prognosis. CRBN methylation and expression serve as important pancancerprognostic biomarkers, highlighting the potential for epigenetic therapies to restore CRBN function andovercome therapeutic resistance.