The dysregulated YY1-EZH2-RKIP axis in cancer cells and immune evasion

Abstract

We have recently witnessed several milestones in the treatment of a subset of cancer patients with immunotherapy and resulting in significant clinical responses. However, there is a subset that is unresponsive due to resistant factors in the cancer cells that are responsible for immune evasion. The characterization of such factors might lead to novel targeted therapies to restore the anti-tumor immunotherapies. We describe three dysregulated gene products, namely, Yin Yang1 (YY1), EZH2, and RKIP (PEBP1), that play pivotal roles in immune evasion. We report on the various molecular regulatory roles and signaling pathways that lead to the overexpression of YY1 and EZH2 and under expression of RKIP in cancer cells and established cross-talk signaling pathways amongst these three gene products. Such cross-talks established the dysregulated YY1-EZH2-RKIP axis and its pivotal role in the regulation of immune evasion. Thus, this axis is a potentially new therapeutic target to inhibit immune evasion by targeting the inhibition of YY1 or EZH2 or the induction of RKIP. Various agents are discussed to target each of these gene products, alone or in combination, to be investigated preclinically. However, the specific targeting to the tumor cells and sparing normal tissues is challenging, though new approaches are feasible.