Cdc6 as a novel target in cancer: oncogenic potential, senescence and subcellular localisation
AffiliationDivision of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Manchester Cancer Research Centre, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, UK
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AbstractCdc6 is a key replication licencing factor with a pivotal role in regulating the process of DNA replication, rendering it an important investigatory focus in tumourigenesis. Indeed, Cdc6 overexpression has been found to be a feature in certain tumours and has been associated as an early event in malignancies. With a focus on pancreatic cancer, there are evidence of its convergence in downstream pathways implicated in major genetic alterations found in pancreatic cancer, primarily KRAS. There is also data of its direct influence on protumourigenic processes as a transcriptional regulator, repressing the key tumour suppressor loci CDH1 (E-Cadherin) and influencing epithelial to mesenchymal transition (EMT). Moreover, gene amplification of Cdc6 as well as of E2F (an upstream regulator of Cdc6) have also been found to be a key feature in tumours overexpressing Cdc6, further highlighting this event as a potential driver of tumourigenesis. In this review, we summarise the evidence for the role of Cdc6 overexpression in cancer, specifically that of pancreatic cancer. More importantly, we recapitulate the role of Cdc6 as part of the DNA damage response and on senescence-an important antitumour barrier-in the context of pancreatic cancer. Finally, recent emerging observations suggest that the potential of the subcellular localisation of Cdc6 in inducing senescence. In this regard, we speculate and hypothesise potentially exploitable mechanisms in the context of inducing senescence via a novel pathway involving cytoplasmic retention of Cdc6 and Cyclin E.
CitationLim N, Townsend PA. Cdc6 as a novel target in cancer: Oncogenic potential, senescence and subcellular localisation. Int J Cancer. 2020.
JournalInternational Journal of Cancer
- ARID1A suppresses malignant transformation of human pancreatic cells via mediating senescence-associated miR-503/CDKN2A regulatory axis.
- Authors: Li ZY, Zhu SS, Chen XJ, Zhu J, Chen Q, Zhang YQ, Zhang CL, Guo TT, Zhang LM
- Issue date: 2017 Nov 18
- Coordinated activation of the origin licensing factor CDC6 and CDK2 in resting human fibroblasts expressing SV40 small T antigen and cyclin E.
- Authors: Sotillo E, Garriga J, Padgaonkar A, Kurimchak A, Cook JG, Graña X
- Issue date: 2009 May 22
- Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells.
- Authors: Yan Z, DeGregori J, Shohet R, Leone G, Stillman B, Nevins JR, Williams RS
- Issue date: 1998 Mar 31
- Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization.
- Authors: Petersen BO, Lukas J, Sørensen CS, Bartek J, Helin K
- Issue date: 1999 Jan 15
- Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice.
- Authors: Hermann PC, Sancho P, Cañamero M, Martinelli P, Madriles F, Michl P, Gress T, de Pascual R, Gandia L, Guerra C, Barbacid M, Wagner M, Vieira CR, Aicher A, Real FX, Sainz B Jr, Heeschen C
- Issue date: 2014 Nov