Biological significance of the direct cross-talk between transcription factors CP2c and YY1

Abstract

Developmental fate decision and the maintenance of cellular hierarchies and identities are dictated by sophisticated regulatory networks driven by transcription factors (TFs). However, the detailed regulatory networks controlled by crosstalk between TFs are not fully understood. CP2c was initially discovered as a TF that binds to and stimulates transcription from the erythroid cell specific α-globin promoter. CP2c has been known to play an important role in the control of cell proliferation and cell cycle regulating some tissue- or stage-specific target gene expression, and also functions as an oncogene in multiple cancers. Previously, we reported that CP2c directly interacts with another TF YY1. YY1 is known to function as a transcriptional activator or repressor, and exerts its diverse roles in critical cellular activities, and overexpression of YY1 has been observed in various cancers. Importantly, CP2c and YY1 mutually repress their specific target gene expression YY1 suppresses transcriptional activity of cp2c by direct interaction with the DNA-bound CP2c, whereas CP2c indirectly suppresses transcriptional activity of YY1 by degrading the nuclear YY1 protein in solution via 20S proteasome pathway. We have speculated that functional cross-antagonism between CP2c and YY1 affects, in part, their differential cellular distribution in normal differentiation and in tumorigenesis. In this study, as an initial effort to understand the biological significance of functional cross-antagonism between CP2c and YY1 in cell differentiation and fate decision, we analyzed cellular distribution of CP2c and YY1 during spermatogenesis and hepatocarcinogenesis. YY1 strongly localizes in the spermatogonial stem cells and co-localizes heterogeneously with CP2c to permit spermatogenesis, suggesting that YY1 is essential for stemness of spermatogonial stem cells whereas CP2c is critical for the commitment of spermatogonia and during the progression of spermatogonia to spermatids. Meanwhile, when we analyzed the expression of CP2c and YY1 in normal liver (n=16), adjacent noncancerous liver (n=48) and HCC (n=136) tissues, CP2c was expressed at significantly higher levels in HCC tissues than normal liver or adjacent noncancerous (ADJ) liver tissues. Nuclear YY1 expression was also significantly higher in HCC samples than normal or ADJ liver tissues. In further, patients with high expression of both CP2c and nuclear YY1 usually had a shorter median survival time and worse disease free survival (DFS) prognosis than other patients, suggesting that combined detection of CP2c and nuclear YY1 is a good prognostic marker in HCC patients. Collectively, differential cellular distribution of CP2c and YY1 in normal development and in tumorigenesis that is caused in part by functional cross-antagonism between CP2c and YY1 might be important for fine-tuning cell fate decisions in normal development and in tumorigenesis.