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  • Review Article
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CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

Key Points

  • CUT-like homeobox 1 (CUX1) undergoes loss-of-heterozygosity (LOH) and loss-of-function somatic point mutations in several cancers. As no mutations are found in the remaining allele, CUX1 seems to be a haploinsufficient tumour suppressor gene.

  • Copy number gains are much more frequent than losses in cancers arising from many different types of tissue, including cancers that have a high frequency of loss-of-function mutations. Increased CUX1 copy number and expression levels are associated with shorter disease-free survival.

  • The accumulated evidence suggests that decreased CUX1 expression facilitates tumour initiation, whereas increased CUX1 expression promotes tumorigenic progression.

  • One CUX1 protein isoform functions as an ancillary factor in base excision repair. Other CUX1 isoforms function as transcriptional repressors or activators, depending on promoter context.

  • Cellular functions of CUX1 that promote tumour development involve cell cycle progression, cell migration and invasion, resistance to apoptosis, promotion of bipolar mitosis in the presence of multiple centrosomes, accelerated repair of oxidative DNA damage and modulation of the tumour microenvironment.

  • Cellular functions of CUX1 that suppress tumour development include inhibition of the PI3K–AKT pathway and a direct role in base excision repair.

Abstract

CUT-like homeobox 1 (CUX1) is a homeobox gene that is implicated in both tumour suppression and progression. The accumulated evidence supports a model of haploinsufficiency whereby reduced CUX1 expression promotes tumour development. Paradoxically, increased CUX1 expression is associated with tumour progression, and ectopic CUX1 expression in transgenic mice increases tumour burden in several tissues. One CUX1 isoform functions as an ancillary factor in base excision repair and the other CUX1 isoforms act as transcriptional activators or repressors. Several transcriptional targets and cellular functions of CUX1 affect tumorigenesis; however, we have yet to develop a mechanistic framework to reconcile the opposite roles of CUX1 in cancer protection and progression.

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Figure 1: Structure of the CUT-like homeobox 1 (CUX1) gene, mRNAs and proteins.
Figure 2: Mechanisms of action in cancer.
Figure 3: CUT-like homeobox 1 (CUX1) copy number variations in human tumours and cancer cell lines.
Figure 4: Biochemical activities implicated in tumour suppression.

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Acknowledgements

This work was supported by Grant number MOP-98010 from the Canadian Institutes of Health Research (CIHR) to A.N.; Z.M.R. was supported by the Fonds de la recherche du Québec-Santé (FRQS). This Review is dedicated to the memory of Rosalind Goodman.

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Glossary

Loss-of-heterozygosity

(LOH). Loss of one allele of a gene when the original two alleles can be distinguished. This is common for tumour suppressor genes when the other allele is mutated, although it may occur without mutation of the remaining allele.

Haploinsufficient

Describing loss or mutagenic inactivation of a single allele of a tumour suppressor gene that hastens tumorigenicity.

Non-oncogene addictions

The concept of 'non-oncogene addiction' describes the heightened dependency of tumour cells on the normal cellular functions of certain genes that are not themselves classical oncogenes.

The Knudson two-hit model

A model that stipulates that inactivation of a tumour suppressor gene requires two events: the loss of one allele, in a process called loss-of-heterozygosity (LOH); and the occurrence of inactivating mutation in the second allele. However, a dominant-negative mutation may be sufficient to inactivate the function of a tumour suppressor, as in the case of TP53.

Glomerulosclerosis

The scarring or hardening of the glomeruli, which are the blood vessels in the kidney.

Interstitial fibrosis

A disease that is characterized by increased proliferation and accumulation of extracellular matrix.

Merotelic chromosome attachments

These attachments occur when a single kinetochore is attached to microtubules emanating from both spindle poles. If not corrected, merotelic attachments may result in whole chromosome missegregation and aneuploidy.

Synthetic lethal

A situation in which the inactivation of a pathway by a genetic means is lethal to cells that harbour a mutation in an different pathway but is not overly detrimental to normal cells.

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Ramdzan, Z., Nepveu, A. CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers. Nat Rev Cancer 14, 673–682 (2014). https://doi.org/10.1038/nrc3805

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