The Yin and Yang of YY1 in tumor growth and suppression

Abstract

Yin Yang-1 (YY1) is a zinc finger protein and member of the GLI-Kruppel family that can activate or inactivate gene expression depending on interacting partners, promoter context and chromatin structure, and may be involved in the transcriptional control of ∼10% of the total mammalian gene set. A growing body of literature indicates that YY1 is overexpressed in multiple cancer types and that increased YY1 levels correlate with poor clinical outcomes in many cancers. However, the role of YY1 in the promotion or suppression of tumor growth remains controversial and its regulatory effects may be tumor cell type dependent at least in experimental systems. The molecular mechanisms responsible for the apparently conflicting roles of YY1 are not yet fully elucidated. This review highlights recent advances in our understanding of regulatory insights involving YY1 function in a range of cancer types. For example, YY1's roles in tumor growth involve stabilization of hypoxia-inducible factor HIF-1α in a p53 independent manner, negative regulation of miR-9 transcription, control of MYCT1 transcription, a novel miR-193a-5p-YY1-APC axis, intracellular ROS and mitochondrial superoxide generation, p53 reduction and EGFR activation, control of genes associated with mitochondrial energy metabolism and miRNA regulatory networks involving miR-7, miR-9, miR-34a, miR-186, miR-381, miR-584-3p and miR-635. On the other hand, tumor suppressor roles of YY1 appear to involve YY1 stimulation of tumor suppressor BRCA1, increased Bax transcription and apoptosis involving cytochrome c release and caspase-3/-7 cleavage, induction of heme oxygenase-1, inhibition of pRb phosphorylation and p21 binding to cyclin D1 and cdk4, reduced expression of long noncoding RNA of SOX2 overlapping transcript, and MUC4/ErbB2/p38/MEF2C-dependent downregulation of MMP-10. YY1 expression is associated with that of cancer stem cell markers SOX2, BMI1 and OCT4 across many cancers suggesting multidynamic regulatory control and groups of cancers with distinct molecular signatures. Greater understanding of the mechanistic roles of YY1 will in turn lead to the development of more specific approaches to modulate YY1 expression and activity with therapeutic potential.