The Quest for the 1P36 Tumor Suppressor

Review The Quest for the 1p36 Tumor Suppressor Anindya Bagchi and Alea A. Mills Cold Spring Harbor Laboratory, Cold Spring Harbor, New York Abstract identity are rare. One idea is that 1p36 is inherently unstable. 1p36 Genomic analyses of late-stage human cancers have uncov- Another possibility is that several tumor suppressors work ered deletions encompassing 1p36, thereby providing an together and, therefore, that loss of a combination of these genes is extensive body of literature supporting the idea that a potent a prerequisite for cancer. Because hereditary cancer predisposition tumor suppressor resides in this interval. Although several syndromes do not exist for this genomic region, linkage-based genes have been proposed as 1p36 candidate tumor suppres- methodologies that were so crucial for discovering tumor suppressors such as retinoblastoma, are not helpful for identifying tumor sors, convincing evidence that their encoded products protect 1p36 from cancer has been scanty. A recent functional study iden- suppressors in this interval. In short, has presented a major tified chromodomain helicase DNA-binding protein 5 (CHD5)as challenge for the cancer community. a novel tumor suppressor mapping to 1p36. Here, we discuss evidence supporting the tumor-suppressive role of CHD5. Pinpointing the Tumor-Suppressive Region Together, these findings suggest that strategies designed to The underlying assumption for the approach that we took was enhance CHD5 activity could provide novel approaches for that there was a region of 1p36 that when deleted would predispose treating a broad range of human malignancies. [Cancer Res to cancer. Therefore, increased tumorigenicity would provide the 2008;68(8):2551–6] functional readout needed to reveal the location of the tumor suppressor. Chromosome engineering, a Cre/loxP-based methodol- Introduction ogy(23)reviewedbyMillsandBradley(24),wasusedto Deletions of the short arm of human chromosome 1 were first systematically delete regions of the mouse genome corresponding 1p36 reported in neuroblastoma in 1977 (1), presaging a flurry of reports to human (25). This seemed a logical approach because genes indicating that the region referred to as 1p36 is frequently deleted are conserved between mouse and man in this region of the 1p36 in a broad range of human cancers, including those of neural, genome, with genes present on human mapping to distal epithelial, and hematopoietic origin (Fig. 1; refs. 2–22). These mouse chromosome 4 (Fig. 2). This strategy identified a tumor- findings suggest that loss of a tumor suppressor mapping to this suppressive interval that when deleted caused enhanced prolifer- region is a critical event in tumorigenesis. Because such a diverse ation, loss of contact inhibition, and spontaneous immortalization array of human cancers has been associated with deletion of 1p36, in cultured cells, hallmarks of increased tumorigenic potential. in vivo loss or inactivation of this region might be a common initiating These cellular phenotypes culminated as cancer ; mice hete- event for several malignancies. The search for the 1p36 tumor rozygous for this deletion developed spontaneous tumors, including suppressor has led to some exciting candidates (Fig. 1). Although many types associated with deletion of the corresponding region in some of these proposed tumor suppressors have tumor-protective humans. Further functional evidence that this region harbored a capabilities in specific cellular contexts, none can account for the potent tumor suppressor was garnered when it was discovered that wide range of tumor types that have been associated with the 3 mice engineered to have an extra copy of this region had excessive decades of literature documenting 1p36 deletions. Hence, the tumor suppression. Three copies of this interval caused an increase search for the 1p36 tumor suppressor has continued. in the tumor-suppressive mechanisms of cellular senescence in in vivo Why has it been so difficult to identify the tumor suppressor in cultured cells and markedly enhanced apoptosis . This this region of the genome? One reason could be that more than one combined loss-of-function and gain-of-function approach identified 1p36 1p36 tumor suppressor exists. Support for this idea is that although a potent tumor-suppressive region corresponding to human . the prevalence of tumor-derived deletions attests to 1p36 loss as being an important event in cancer, these deletions do not always Identifying the Tumor Suppressor in the Interval overlap and therefore fail to identify a single genomic interval Although a tumor-suppressive region of mouse chromosome 4 (Fig. 1). Perhaps distinct tumor suppressors function tissue spe- had been identified, this genomic interval was 4.3 Mb and cifically; this might be the reason that the various malignancies in encompassed 52 genes (25). Therefore, the next phase of this work which 1p36 deletions have been documented cannot be explained was to identify the tumor suppressor in the interval. It had been by any of the individual candidate tumor suppressors described to shown that cells with an extra copy of the region proliferated very date. A feature of most late-stage tumors with 1p36 deletions is poorly in culture and that this proliferative defect was rescued by that the interval involved is typically extremely large, often encom- ‘‘correcting’’ dosage of the interval (i.e., cells with an extra copy of passing the entire short arm; therefore, informative tumors that the region on one chromosome and a deletion of the same interval might reveal the location of the tumor suppressor and lead to its on the other chromosome were effectively diploid for that region). Mice carrying both a deletion and a duplication of the 4.3-Mb Requests for reprints: Alea A. Mills, Cold Spring Harbor Laboratory, One interval were viable and fertile, and cells from these animals Bungtown Road, Cold Spring Harbor, NY 11724. Phone: 516-367-6910; E-mail: mills@ proliferated at rates comparable with those of wild-type cells. cshl.edu. I2008 American Association for Cancer Research. Therefore, Occam’s razor—the principle that the simplest solution doi:10.1158/0008-5472.CAN-07-2095 is usually the best one—posed the possibility that cells with an www.aacrjournals.org 2551 Cancer Res 2008; 68: (8). April 15, 2008 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2008 American Association for Cancer Research. Cancer Research 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 is shown to scale. Several 1p36 tumor suppressors have been proposed. Many of the deletions encompass CHD5 (dotted line), whereas others are clearly in distinct regions of 1p36. extra copy of the region proliferated poorly because they had members of the chromodomain superfamily of proteins (26). increased expression of a single gene within the interval. This CHD5 is one of nine members of the CHD family, named because of meant that the tumor suppressor could be identified by syste- their unique combination of chromatin organizing modulator, matically reducing expression of candidate genes in cells with an helicase, and DNA-binding domains. The CHD family can be extra copy of the interval. The assay was simply looking for the further subdivided; CHD5 is similar to CHD3 and CHD4 in that it is gene that restored proliferation when its dosage was reduced. endowed with plant homeodomain motifs (27). Interestingly, CHD3 Genes were prioritized based on gene ontology terms, and RNA and CHD4 are components of the nucleosome remodeling interference (RNAi) was then used to reduce expression of the top complex, an assembly of proteins that remodels chromatin by candidates in the region (25). Knockdown of all but one gene tested sliding nucleosomes out of the way, thereby providing polymerase failed to rescue the proliferative defect. For example, knockdown of with the access needed to activate gene expression. Other than this p73, Dnajc11, and Camta1, genes within the interval that had homology between CHD5 and previously described chromatin previously been proposed as 1p36 tumor suppressor candidates, remodeling proteins, very little functional data existed for this failed to enhance proliferation, thereby excluding these genes as protein. How might this hypothesized chromatin remodeling being responsible for the tumor-suppressive phenotypes observed. protein function to prevent cancer? In contrast, two different hairpins against chromodomain helicase DNA-binding protein 5 (Chd5) effectively restored proliferation to Chd5 Is a Master Regulator of a Tumor-Suppressive these poorly proliferating cells and even enhanced proliferation of Network wild-type cells. This identified Chd5 as the tumor suppressor The tumor-suppressive region modulates p16Ink4a/Rb- and candidate in the region. p19Arf/p53-mediated pathways. To explore the mechanism whereby Chd5 protects from tumorigenesis, models with loss and CHD5 Is a Proposed Chromatin Remodeler gain of the region encompassing Chd5 were first examined (25). The Human CHD5 had previously been proposed to function as a first clue was that the phenotypes of poor proliferation, enhanced chromatin remodeling protein based on its homology with cellular senescence, and augmented apoptosis that were caused

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