The quest for the 1p36 tumor suppressor

Abstract

Genomic analyses of late-stage human cancers have uncovered deletions encompassing 1p36, thereby providing an extensive body of literature supporting the idea that a potent tumor suppressor resides in this interval. Although several genes have been proposed as 1p36 candidate tumor suppressors, convincing evidence that their encoded products protect from cancer has been scanty. A recent functional study identified chromodomain helicase DNA-binding protein 5 (CHD5) as a novel tumor suppressor mapping to 1p36. Here, we discuss evidence supporting the tumor-suppressive role of CHD5. Together, these findings suggest that strategies designed to enhance CHD5 activity could provide novel approaches for treating a broad range of human malignancies.

Figure 1. 1p36 is deleted in a variety of human cancers

The distal portion of the short arm of human chromosome 1 is shown, with the 24.9 Mb 1p36 region depicted by a gray rectangle. A subset of deletions that have been reported in a variety of epithelial- (green), neural associated- (blue), and lymphoid (red) malignancies are shown to scale. A number of 1p36 tumor suppressors have been proposed. Many of the deletions encompass CHD5 (dotted line), whereas others are clearly in distinct regions of 1p36.

Figure 2. A number of independent studies support a tumor suppressive role for CHD5

Genes mapping to 1p36 (upper panel) are contained within a conserved linkage group on distal mouse chromosome 4 (lower panel). Mouse models with gain- and loss of a 4.3 Mb region of mouse chromosome 4 identify a potent tumor suppressive region corresponding to a 5.7 Mb region of human 1p36; this overlaps with a 5.4 Mb mcr in human glioma (green) (25). A more recent study identifies a 2.1 Mb mcr in neuroblastoma (red) (30). An independent study identifies a 3.9 Mb mcr in a genomically unstable mouse model of lymphoma, and also identifies a 0.34 Mb mcr in human T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) (blue) (29). Combined, these studies identify a 2.5 Mb and a 0.34 Mb mcr in mouse and humans that encompass Chd5 and CHD5, respectively (arrows). Note that neither p73 nor miR34 map within the mcr. In addition, CHD5 is mutated in both glioma (red asterisk) (30) and breast cancer (orange asterisks) (31). Each asterisk depicts a distinct mutation.