Opposing roles of YY1 and RKIP in cancer progression and therapy resistance

Abstract

Yin Yang 1 (YY1) and Raf kinase inhibitory protein (RKIP, encoded by PEBP1) are multifunctional regulators with antagonistic roles in tumor biology. YY1 functions as a context-dependent transcription factor and chromatin organizer, integrating enhancer–promoter looping and super-enhancer activity to drive oncogenic transcriptional programs, immune evasion, and therapy resistance. By contrast, RKIP restrains the NF-κB, MAPK and STAT3 pathways, suppressing epithelial–mesenchymal transition, metastasis, and chemoresistance. Recent pan-cancer transcriptomic analyses highlight a recurrent pattern of YY1 upregulation and RKIP downregulation, with inverse correlations in several tumor types (e.g., lung, colorectal and kidney). Clinically, high YY1 expression is associated with poor survival and diminished responses to chemotherapy, TRAIL, and immune checkpoint blockade, whereas high RKIP predicts improved outcomes and restored therapeutic sensitivity. YY1 and RKIP also modulate key immune compartments: YY1 promotes Treg expansion, myeloid-derived suppressor cell (MDSC) accumulation, tumor-associated macrophage (TAM) polarization, and impaired antigen presentation, while RKIP counteracts these processes and enhances cytotoxic T and NK cell activity. Therapeutically, YY1 can be targeted through BET/p300 inhibitors, emerging PROTAC degraders, and RNA- or CRISPR-based approaches; RKIP restoration is under investigation via kinase and pathway modulators. Together, YY1 and RKIP constitute a regulatory axis with prognostic and predictive value, offering potential for biomarker-driven patient stratification and novel therapeutic strategies in precision oncology.