Loss of Both CDKN2A and CDKN2B Allows for Centrosome Overduplication in Melanoma

Abstract

Centrosomes duplicate only once in coordination with the DNA replication cycle and have an important role in segregating genetic material. In contrast, most cancer cells have centrosome aberrations, including supernumerary centrosomes, and this correlates with aneuploidy and genetic instability. The tumor suppressors p16 (CDKN2A) and p15 (CDKN2B) (encoded by the familial melanoma CDKN2 locus) inhibit CDK4/6 activity and have important roles in cellular senescence. p16 is also associated with suppressing centrosomal aberrations in breast cancer; however, the role of p15 in centrosome amplification is unknown. Here, we investigated the relationship between p15 and p16 expression, centrosome number abnormalities, and melanoma progression in cell lines derived from various stages of melanoma progression. We found that normal human melanocyte lines did not exhibit centrosome number abnormalities, whereas those from later stages of melanoma did. Additionally, under conditions of S-phase block, p15 and p16 status determined whether centrosome overduplication would occur. Indeed, removal of p15 from p16-negative cell lines derived from various stages of melanoma progression changed cells that previously would not overduplicate their centrosomes into cells that did. Although this study used cell lines in vitro, it suggests that, during clinical melanoma progression, sequential loss of p15 and p16 provides conditions for centrosome duplication to become deregulated with consequences for genome instability.

Transcriptional signatures underlying dynamic phenotypic switching and novel disease biomarkers in a linear cellular model of melanoma progression

“…Patel and colleagues [45] have demonstrated that the loss of both Cdkn2a and Cdkn2b contributes to genome instability in late stages of melanoma progression. While the consequences of CDKN2A inhibition to melanoma pathogenesis are better known than those of CDKN2B , the p15 protein encoded by CDKN2B is highly expressed in benign melanocytic nevi, and its loss promotes the transition from benign nevus to melanoma [46] .…”

Causes, consequences and clinical significance of aneuploidy across melanoma subtypes

“… Cell cycle defects that can lead to aneuploidy in melanoma. Defects include centrosomal amplification ( 29 , 81 , 82 ), replication stress ( 28 ), G2 decatenation failure ( 83 – 85 ) and SAC dysregulation ( 26 ). ( 27 , 86 ).…”

“…Using immunofluorescence to visualize 79 melanoma tissue microarrays, Denu et al ( 81 ) reported that CA is prevalent in melanoma and arises mainly from centriole overduplication (as opposed to cytokinesis failure or other mechanisms of failed mitosis), albeit a lack of association of expression of Polo-like Kinase 4 - PLK4 , a main driver of centriole duplication – with CA. A later study utilizing melanoma cell lines across different stages of melanoma progression implicated sequential loss of Cyclin Dependent Kinase Inhibitor genes CDKN2A and CDKN2B with CA ( 29 ). Based on a centrosome duplication assay, double negative cell lines for p16 and p15 (encoded by CDKN2A and CDKN2B , respectively) overduplicated centrosomes, suggesting that both proteins need to be absent for centrosome overduplication to occur.…”

“…Several defects in mechanisms of the cell cycle that can result in chromosomal mis-segregation and aneuploidy have been identified in melanoma. Importantly, key driver mutations such as BRAF V600E ( 26 , 27 ), KIT K642E ( 28 ) and loss of CDKN2 ( 29 ) have been implicated with such defects including dysregulation in metaphase to anaphase transition, replication stress and centrosomal amplification.…”

Screening of potential novel candidate genes in schwannomatosis patients

“…CDKN2A encodes two proteins, p16INK4a and the alternatively translated p14ARF, both of which have a role in tumor suppression, through regulation of Rb and p53 pathways (Quelle et al, 1995; Zhang et al, 1998a,b). Loss of function of both CDKN2A and its tandemly linked gene CDKN2B , which encodes p15INK4b, another regulator of the Rb pathway (Hannon & Beach, 1994), have been implicated in a variety of cancers from central nervous system (CNS) tumors, including schwannomas (Ali et al, 2021; Almeida et al, 2008; Cancer Genome Atlas Research, 2008; S. Zhang et al, 1996) pancreatic cancer, renal cancer, and melanoma (Goldstein et al, 2006; Jafri et al, 2015; McNeal et al, 2015; Patel et al, 2020; Tu et al, 2018). Indeed, CDKN2A is one of the main susceptibility genes for familial melanoma with both point mutations and gene deletions implicated in pathogenesis (Goldstein & Tucker, 1997; Hussussian et al, 1994; Kamb et al, 1994; Pollock et al, 1998; Whiteman et al, 1997).…”