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1P36 Tumor Suppression—A Matter of Dosage?

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1P36 Tumor Suppression—A Matter of Dosage? Published OnlineFirst November 29, 2012; DOI: 10.1158/0008-5472.CAN-12-2230 Cancer Review Research 1p36 Tumor Suppression—A Matter of Dosage? Kai-Oliver Henrich, Manfred Schwab, and Frank Westermann Abstract A broad range of human malignancies is associated with nonrandom 1p36 deletions, suggesting the existence of tumor suppressors encoded in this region. Evidence for tumor-specific inactivation of 1p36 genes in the classic "two-hit" manner is scarce; however, many tumor suppressors do not require complete inactivation but contribute to tumorigenesis by partial impairment. We discuss recent data derived from both human tumors and functional cancer models indicating that the 1p36 genes CHD5, CAMTA1, KIF1B, CASZ1, and miR-34a contribute to cancer development when reduced in dosage by genomic copy number loss or other mechanisms. We explore potential interactions among these candidates and propose a model where heterozygous 1p36 deletion impairs oncosuppressive pathways via simultaneous downregulation of several dosage-dependent tumor suppressor genes. Cancer Res; 72(23); 6079–88. Ó2012 AACR. Introduction (Fig. 1; refs. 1, 17–29). Despite extensive 1p36 candidate gene Deletions of the distal short arm of chromosome 1 (1p) are sequence analyses, success was limited for identifying tumor- fi frequently observed in a broad range of human cancers, speci c mutations in neuroblastomas or other malignancies, including breast cancer, cervical cancer, pancreatic cancer, which led some to conclude that a deletion mapping approach pheochromocytoma, thyroid cancer, hepatocellular cancer, was unlikely to deliver tumor suppressor genes. Many tumor colorectal cancer, lung cancer, glioma, meningioma, neuro- suppressor genes, however, do not require inactivation in a blastoma, melanoma, Merkel cell carcinoma, rhabdomyosar- classic "two-hit" manner but contribute to tumor development coma, acute myeloid leukemia, chronic myeloid leukemia, and when their dosage is reduced, sometimes only subtly, by non-Hodgkin lymphoma (1, 2). These nonrandom aberrations mechanisms such as copy number change, transcriptional suggest that loss of genetic information mapping to this region repression, epigenetic downregulation, or aberrant miRNA contributes to cancer development. This is supported by regulation (30). Unlike in a classic "two-hit" mutational inac- fi constitutional 1p aberrations in neuroblastoma patients (3, tivation scenario, de nite proof for dosage-sensitive tumor 4) and the association of 1p deletion with poor survival of suppressor gene involvement is not offered by a single straight neuroblastoma (5), breast cancer (6, 7), and colon cancer (8, 9) forward assay. Instead, evidence must be accumulated from patients. Deletion of 1p in premalignant lesions and/or early genetic, epigenetic, and transcriptional analyses of human tumor stages of colorectal, breast, and hepatocellular cancer tumors and functional in vitro and in vivo assays. This review fi (10–12) points to a role for 1p genes during the early steps of discusses ve 1p36 genes, CHD5, CAMTA1, KIF1B, CASZ1, and carcinogenesis in these entities. This is supported by loss of 1p miR-34a, recently suggested as tumor suppressor candidates material during in vitro progression in a cell culture model of and likely to be impaired by partial reduction as suggested by colon carcinogenesis (13). Furthermore, transfer of 1p chro- both their status in human cancers and their activity in mosomal material suppresses tumorigenicity of both neuro- functional cancer models. blastoma and colon carcinoma cells (14, 15). Since the first report of 1p deletions in neuroblastomas in CHD5 1977 (16), smallest regions of overlapping heterozygous dele- Chromodomain helicase DNA binding (CHD) genes encode a tions (SRO) have been defined in various tumor entities in the class of ATPase-dependent DNA-binding proteins interacting pursuit of cancer-related genes. That 1p36 is a hot spot of with histones to modulate chromatin structure and transcrip- chromosomal aberrations became clear early on (1), with the tion. CHD5 resides in 1p36.31, is preferentially expressed in most detailed mapping picture appearing for neuroblastoma neuronal tissues, and its product regulates genes involved in neuronal function, cell-cycle control, and chromatin remodel- ing (31). Functional evidence for a tumor suppressive role of mouse Chd5 derives from an elegant approach using chromo- Authors' Affiliation: Division of Tumor Genetics B030, German Cancer Research Center, Heidelberg, Germany some engineering to generate mouse models with loss or gain of genomic regions corresponding to human 1p36 (22). Dele- Corresponding Author: Kai-Oliver Henrich, Division of Tumor Genetics B030, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 tion of a Chd5-containing 4.3 Mb genomic subinterval, corre- Heidelberg, Germany. Phone: 496-221-423-220; Fax: 496-221-423-277; sponding to 5.7 Mb of human 1p36, enhanced proliferation, loss E-mail: [email protected] of contact inhibition, spontaneous immortalization, and sen- doi: 10.1158/0008-5472.CAN-12-2230 sitivity to oncogenic transformation of cultured mouse embry- Ó2012 American Association for Cancer Research. onic fibroblasts. Mice with heterozygous deletion of this www.aacrjournals.org 6079 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst November 29, 2012; DOI: 10.1158/0008-5472.CAN-12-2230 Henrich et al. 0 Mb 5 Mb 10 Mb 15 Mb 20 Mb 25 Mb 1p36.33 1p36.32 1p36.31 1p36.23 1p36.22 1p36.21 1p36.13 1p36.12 1p36.11 p73 CAMTA1 CHD5 p73 CHD5 KIF1B CASZ1 miR-34a CAMTA1 Schwab et al., 1996 (review) (1) Neuronal D1S47 D1S244 miR-34a genes Caron et al., 2001 (17) D1S1615 MYCN / MYC CASZ1 Bauer et al., 2001 (18) D1S2731 D1S2666 White et al., 2005 (19) BMI1 EZH2 D1S214 D1S2660 Neuroblastoma Ohira et al., 2000 (homozygous, cell line) (20) CADM1 miR-101 HDNB1 KIF1B D1S2736 (11q23) (1p31) Ejeskär et al., 2001 (germ cell tumors + NB) (21) D1S508 D1S244 1p36-encoded Bagchi et al., 2007 (22) Barbashina et al., 2005 (23) D1S2694 D1S2666 Glioma Felsberg et al., 2004 (24) D1S482 D1S489 D1S2633 D1S2642 Pheochromocytoma; Edström Elder et al., 2000 (25) D1S1612 Melanoma; Poetsch et al., 2003 (26) D1S214 D1S253 D1S243 D1S468 Small cell lung cancer; Girard et al., 2000 (27) D1S214 Non-small cell lung cancer; Girard et al., 2000 (27) D1S199 Other entities Breast cancer; Bieche et al., 1999 (28) D1S243 D1S468 D1S160 D1S244 Colorectal cancer; Thorstensen et al., 2000 (29) D1S228 D1S2647 Figure 1. Localization of tumor suppressor candidates p73, CHD5, CAMTA1, miR-34a, KIF1b, and CASZ1 with respect to 1p36 alterations in human cancers. Horizontal bars illustrate the extension of commonly deleted regions; short vertical bars at their end represent the first nondeleted locus. Only size (5.4 Mb) and chromosomal extension (1p32.32–1p36.22) are available for the region identified by Bagchi et al. (22). Genomic positions correspond to the UCSC genome browser, assembly Feb. 2009 (GRCh37/hg19). Gray box, model illustrating potential interactions between 1p36 tumor suppressor candidates. subinterval were prone to hyperplasia in a variety of tissues effects of the engineered deletion, including enhanced prolif- (22). Duplication of this subinterval in mouse embryonic eration, sensitivity to oncogenic transformation, and inhibition fibroblasts inhibited proliferation and increased the senescent of p19Arf/p53 (22). This suggests that Chd5 is a dose-dependent cell fraction. Mice with subinterval duplication had develop- gene within the identified 4.3 Mb genomic subinterval that mental abnormalities characterized by an increased apoptotic mediates the tumor suppressive mechanisms seen in mouse cell fraction in various tissues, including the neural tube (22). models. The functional role of human CHD5 in a cancer The identified subinterval includes 52 genes. Among 11 tested background was analyzed in neuroblastoma cells, where its candidate genes, knockdown of only Chd5 functionally rescued overexpression had no impact on proliferation, morphology, the proliferative defect of mouse embryonic fibroblasts with differentiation, or apoptosis but significantly inhibited clono- duplication of the subinterval. Chd5 knockdown in wild-type genic growth in soft agar and xenograft tumor growth in mice cells induced phenotypic changes closely resembling the (32). The absence of an impact on proliferation may indicate an 6080 Cancer Res; 72(23) December 1, 2012 Cancer Research Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst November 29, 2012; DOI: 10.1158/0008-5472.CAN-12-2230 1p36 Tumor Suppression—A Matter of Dosage? already impaired p14Arf (human p19Arf homolog)/p53 pathway nostic information to existing risk stratification (46). Conse- in these cells, a defect frequently seen in neuroblastomas (33). quently, CAMTA1 is included in most recent prognostic neu- CHD5 is one of 23 genes mapping to a 2 Mb SRO in neuro- roblastoma expression classifiers (51–54). Low CAMTA1 blastoma (34) and a 5.4 Mb SRO spanning 1p36.32 to 1p36.22 expression is also significantly associated with shorter survival in glioma (Fig. 1; refs. 22, 34). An SRO containing Chd5 was in glioblastoma patients (50), and, intriguingly, low CAMTA1 identified in a lymphoma mouse model with chromosomal expression emerged as a new independent predictor of poor instability, and syntenic CHD5-containing deletions were dis- outcome
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