Targeting the Y/CCAAT box in cancer: YB-1 (YBX1) or NF-Y?

Abstract

The Y box is an important sequence motif found in promoters and enhancers containing a CCAAT box - one of the few elements enriched in promoters of large sets of genes overexpressed in cancer. The search for the transcription factor(s) acting on it led to the biochemical purification of the nuclear factor Y (NF-Y) heterotrimer, and to the cloning - through the screening of expression libraries - of Y box-binding protein 1 (YB-1), an oncogene, overexpressed in aggressive tumors and associated with drug resistance. These two factors have been associated with Y/CCAAT-dependent activation of numerous growth-related genes, notably multidrug resistance protein 1. We review two decades of data indicating that NF-Y ultimately acts on Y/CCAAT in cancer cells, a notion recently confirmed by genome-wide data. Other features of YB-1, such as post-transcriptional control of mRNA biology, render it important in cancer biology.

Figure 1

Scheme of NF-Y subunits and YB-1

Figure 2

Y/CCAAT ‘evolution' over time

Figure 3

Enriched TFBS in YB-1- or NF-Y-regulated genes. Data of gene expression profilings of different cell lines, reported by Lasham et al., were analyzed by pscan (upper panels). In the lower panels, a similar analysis is reported on gene expression profiles of HCT116 cells inactivated with shNF-YA or shNF-YB (Benatti et al.)

Figure 4

Presence of YB-1 and NF-Y peaks in YB-1-regulated genes. YB-1-regulated genes, as summarized by Eliseeva et al., were analyzed for the presence of YB-1 peaks in the YB-1 ChIP-Seq data reported by Astanehe et al., and for NF-Y peaks present in ENCODE data of K562, HeLa-S3 and GM12878 cells (Wang et al. and Fleming and Struhl, submitted for publication)

Figure 5

Scheme of mechanisms of gene expression control by NF-Y and YB-1