The role of Anaphase Promoting Complex activation, inhibition and substrates in cancer development and progression

APC function

The APC is most often considered in terms of its mitotic functions. However, there are many ancillary functions that are performed by the APC including: maintaining genomic stability [19, 64–66], regulating interphase progression [67–69] and apoptosis [70, 71]. Dysregulation of these additional functions can be found in cancer. Both of the APC coactivators have tumor related functions; CDC20 is a well-known oncogene which drives improper cell proliferation [36, 49, 72–74], while CDH1 is considered a tumor suppressor that regulates mitotic exit, entrance to S phase, induces quiescence under stress conditions and maintains genomic stability [16, 66, 75, 76]. We performed a BioGRID analysis of CDC27 to begin to understand the network differences between CDC20 and CDH1, as CDC27 is the key entry point for the coactivators; CDC27 recruits both CDC20 and CDH1 into the APC [77, 78] (Figure 1). BioGRID is a biological database detailing protein-protein, genetic and chemical interactions, as well as post-translational modifications (https://thebiogrid.org). This analysis revealed 144 unique nodes for CDC27, with 602 physical edges, 16 genetic edges and 18 combined physical/genetic edges. Each node, which defines a different gene, was searched on PubMed for interactions with the APC, with APC substrates identified that were uniquely targeted for degradation by CDC20 and/or CDH1. CDC27 was also found to interact with clusters of signalling and trafficking molecules, stress response and DNA repair proteins, CDH1/CDC20 regulators, SAC components, and proteins involved in DNA and RNA processes. This variety of interactors validates the many roles the APC has been described to fulfill.

Figure 1. CDC27 network interactors. The BioGRID database was searched for CDC27 interactors. The search resulted in 144 protein nodes (blue circles) that interact with CDC27, producing 602 physical edges (yellow lines), 16 genetic edges (green lines) and 18 physical/genetic edges (purple lines). An edge is the line connecting 2 proteins. Many proteins have multiple interactors, generating multiple edges for a single protein. The search was done with the minimum evidence filter set at 1 (see Supplementary Figure 1 for raw data). Proteins that only interacted with CDC27 (1 edge) were lost when the filter was set at 2 and were not included in this analysis. Each node was manually manipulated for this clustering exercise.

Subsequent BioGRID searches were performed for CDC20 and CDH1 separately to specifically identify common and unique interactors for the 2 coactivators. One hundred and eighty one and 175 interaction nodes were identified for CDH1 and CDC20, respectively, resulting in 819 edges for CDH1, and 919 edges for CDC20. Nodes define proteins interacting with CDC20 or CDH1, while an edge is a line that connects any 2 proteins. A protein node may have more that 1 edge, resulting in more edges than nodes. Thirteen APC subunits were identified by both the CDC20 and the CDH1 searches. Each protein node was searched on PubMed to identify overlaps with APC function. Any protein that did not overlap with the APC on PubMed was not followed further. Physical interactions identified by BioGRID can be part of global screens where individual hits are not discussed in manuscripts, so are not picked up in PubMed searches. So, while these proteins likely physically associate with CDC20 and/or CDH1, not enough information is available to discern the mechanism of association. Further, many proteins may not be direct interactors, but interact through intermediaries defined by complexes. For this analysis we focused on proteins involved in APC inhibition (Figure 2), APC activation (Figure 3) or are potential APC substrates (Figure 4).

Figure 2. Protein inhibitors of the APC that function through CDC20 and/or CDH1. The BioGRID database was separately searched for CDC20 and CDH1 interactors. To avoid confusion with the cadherin 1 gene (also called CDH1), the alias FZR1 was used to search for the CDH1 coactivator. 181 nodes were identified for FZR1, identifying 801 physical, and 18 genetic edges (see Supplementary Figure 2). For CDC20, 175 nodes were identified, with 911 physical edges and 8 genetic edges (see Supplementary Figure 3). All protein nodes identified were searched using PubMed. Proteins found to inhibit the APC, but not serve as substrates, are shown here. Proteins unique to CDC20 are shown in red, those unique to CDH1 are shown in blue, and those identified in both searches are shown in green. All APC subunits were identified in both searches. Ph, phosphorylation; Ub, ubiquitination.

APC activation

The CDC20 and CDH1 BioGRID searches also revealed proteins that have not yet been identified as substrates, but have APC activation potential. When SAC activity is no longer required, the complex of MAD2, BUBR1 and BUB3 bound to CDC20 must be disassembled. This process requires ATP, and a number of ATP-dependent activities have been described to assist in the dissolution of the SAC, such as TRIP13, p31^comet and the CCT chaperonin [90]. p31^comet was not identified in the BioGRID searches, but peptides derived from p31^comet have been developed in yeast that bind to the APC and disrupt interaction of CDC20 and CDH1 with the APC [46]. Both TRIP13, and 8 components of the CCT chaperonin (CCT2, CCT3, CCT4, CCT5, CCT6A, CCT7, CCT8 and TCP1) were specifically identified only in the CDC20 search (Figure 3). The CCT chaperonin binds CDC20 and is a necessary factor promoting CDC20 binding to the APC [91]. It was observed that the combined action of the CCT chaperonin with TRIP13 is sufficient to completely disassemble the SAC [90]. TRIP13 has been found to interact with p31^comet to induce checkpoint silencing and localizes to kinetochores [92]. Overexpression of TRIP13 is observed in cancers with poor prognosis and is associated with chromosome instability believed to be due to premature checkpoint silencing.

Figure 3. Protein activators of the APC that function through CDC20 and/or CDH1. The BioGRID database was searched for CDC20 and CDH1 interactors. All protein nodes identified were searched using PubMed. Proteins found to activate the APC, but not serve as substrates, are shown here. Proteins unique to CDC20 are shown in red, those unique to CDH1 are shown in blue, and those identified in both searches are shown in green. PARKIN, when phosphorylated by PLK1, is believed to recruit CDC20 and CDH1 to ubiquitinate APC substrates. Ph, phosphorylation; Ac, acetylation; Ub, ubiquitination.

A number of additional APC activators were specifically identified in the CDC20 search: CKS2, CUEDC2, HDAC6, MDC1 and TRIM33 (Figure 3). CKS2 is a Cell division cycle Kinase Subunit that binds to the CDK1/Cyclin A/B complexes to promote their cell cycle driving function. CKS2 is required for meiosis in mammalian cells and mice lacking CKS2 show reduced meiotic development and defective APC^CDC20 function [93]. As written above, CUEDC2 inhibits APC^CDH1, but can also activate APC^CDC20. During mitosis CUEDC2 is phosphorylated by CDK1 [94]. This allowed phosphorylated CUEDC2 to bind to CDC20, and facilitate its release from the SAC component MAD2, thus activating APC^CDC20. In another study, APC^CDC20 was found to be important for neural development by playing a role in post-mitotic dendrite morphogenesis [95]. This unique APC^CDC20 activity was facilitated by HDAC6, a histone deacetylase that is localized to centrosomes, along with CDC20 in neurons. HDAC6 was required for the polyubiquitination of CDC20, and the activation of APC^CDC20, driving the differentiation of dendrites. MDC1 is a mediator of a DNA damage checkpoint, and was shown to interact specifically with CDC27 [96]. This interaction required phosphorylated CDC27 and was driven by DNA damage. A subsequent study showed that loss of MDC1 resulted in a mitotic arrest that was BUBR1 and ATM signalling independent [97]. Cells lacking MDC1 had impaired APC activity, reduced CDC20 levels, and failure of remnant CDC20 to bind the APC. TRIM33 is a member of the RING (really interesting new gene) domain E3 ligases, and has been described as a transcriptional corepressor involved in SMAD4 signaling [98, 99]. TRIM33 has also been shown to interact specifically with APC^CDC20 and is a component of the mitotic checkpoint complex (MCC), a complex of MAD1, MAD2, BUBR1, BUB3 and CDC20 [100]. The interaction of TRIM33 is complex, as it was shown that TRIM33 will still bind APC in the absence of CDC20, but will not bind APC^CDH1. Further, binding assays revealed that TRIM33 only associated with MCC-APC when the SAC was active, not once it was satisfied. This was interpreted to suggest that TRIM33 is required to promote APC^CDC20 function once the SAC is inactive.

The phosphatase CDC14A and the receptor tyrosine kinase superfamily member EPHA4 both activate the APC through interactions with CDH1. CDH1 is phosphorylated by CDK/Cyclin B complexes, which blocks interaction of CDH1 with the APC. Dephosphorylation of CDH1 by Cdc14 in yeast and CDC14A in mammalian cells relieves the inhibitory pressure and enables APC^CDH1 activation [101]. However, CDC14A does not influence APC^CDC20 function. The EPHA4 receptor is involved in neural homeostatic plasticity through interactions with APC^CDH1 [102]. Elevated synaptic activity triggers the tyrosine phosphorylation of EPHA4, which then interacts with APC^CDH1 to target GLUR1 for degradation to reduce synaptic signalling.

Two additional proteins promote mitotic progression by interacting with both CDC20 and CDH1, but in different ways, SIRT2 and PARKIN. SIRT2 is a protein deacetylase and is a member of the Sir2 family of deacetylases. Sir2 was first studied in yeast as a histone deacetylase, and was shown to have a conserved role in promoting longevity in model systems [103, 104]. SIRT2 has been shown to provide anti-tumor potential by deacetylating both CDC20 and CDH1 to promote their recruitment to the APC and cell cycle progression [65]. Loss of SIRT2 in mouse embryonic fibroblasts (MEFs) resulted in stabilized APC substrates, centrosome amplification, and aneuploidy, with mice lacking SIRT2 experiencing increased tumor development. PARKIN, on the other hand, is a RING domain E3 family member that is capable of mono- and polyubiquitinating substrates, with neuroprotective and tumor suppressor potential [105]. Interactions with the APC coactivators were revealed in a study where MEFs lacking PARKIN were shown to have mitotic defects and high levels of multiple APC substrates, such as PLK1, Aurora A, Aurora B and Cyclin B1, for example [106]. This work also revealed that PARKIN forms complexes with either CDC20 or CDH1 that were independent of the APC. Interestingly, depletion of both PARKIN and APC11 recapitulated CDC20 depletion, whereas depletion of PARKIN or APC11 only partially impaired Cyclin B1 degradation. Taken together, it is apparent that there are multiple complex mechanisms in play to regulate APC function. Shifts in the equilibrium of this balancing act could have significant impacts on cell health and viability.

APC substrates

The nodes identified in the BioGRID analyses of CDC20 and CDH1 were all searched by PubMed for any relationship to “anaphase promoting complex”. The resulting literature was assessed for any signs that the particular protein was unstable and targeted for degradation by either APC^CDC20 or APC^CDH1 or both. This search revealed that 69 of the identified proteins were associated with literature related to degradation by the APC (Figure 4; Table 1). Reviews have been written recently that list APC substrates (25 [107], 46 [32], 16 [108], 13 [38]), but the 69 potential substrates identified here, to the best of our knowledge, is the largest cohort of APC substrates assembled. Literature for the proteins identified here as substrates that were not in previous lists are cited in Table 1 [32, 38, 67, 80, 85, 107–142]. Eight proteins were identified only in the CDC20 BioGRID search, 37 identified only in the CDH1 search, and 24 as targeted by both. OTUD7B was identified in both searches and acts as a cell-cycle regulated deubiquitinase that counters APC function [143]. Confirmation for 5 of the proteins, CCND2, CDK1, CDK2, CDK6 and CDKN2B could not be obtained in the literature. The APC targets CCND1, CDK4, CDK5 and CDKN1A/p21 for degradation, CDK1/2/6 all associate with cyclins that are targeted by the APC, and CKDN2B is a CDK4/6 inhibitor that physically interacts with CDK4/6 [38, 118, 120–122, 134–136]. These proteins are likely substrates, but confirmation requires further analyses. As discussed above, APC^CDC20 and APC^CDH1 are believed to play opposed roles in cancer development, with APC^CDC20 thought to play an oncogenic role [35–38], and APC^CDH1 playing a tumor suppressive role [47–51, 56–62]. To gain further insight into these observations we searched each protein in the APC substrate list for a role in cancer using PubMed. All 69 of the putative substrates have been described as being involved in cancer progression. Of the 69 proteins identified in cancer searches, 9 were described as tumor suppressors (orange lettering in Figure 4) and 60 as possible tumor promoters (white lettering in Figure 4). This suggests that proper APC activity is responsible for the targeted degradation of 60 proteins found elevated in tumors and 9 found reduced in tumors. If CDC20 is involved in tumor formation, then we expected that the bulk of the tumor suppressors targeted by the APC would rely on CDC20 activity, whereas the tumor promoters should be specifically targeted by CDH1. As shown in Figure 4, 4 of the 8 proteins potentially targeted by only APC^CDC20 are described as tumor suppressors in the literature, while 33 of the 37 proteins potentially targeted only by APC^CDH1 are described as oncogenes. Of the 24 proteins potentially targeted by both, all but one has been described as elevated in tumor cells. These observations add significant weight to the idea that the APC plays a critical role in cancer development. It is also clear that the APC could potentially be involved in both tumor promotion and tumor suppression, depending on the activity equilibrium between APC^CDC20 and APC^CDH1.

Figure 4. APC substrates that are unique to CDC20 or CDH1, and those that are acted on by both. The BioGRID database was searched for CDC20 and CDH1 interactors. All protein nodes identified were searched using PubMed. Proteins found to serve as APC substrates are shown here. Proteins unique to CDC20 are shown in red, those unique to CDH1 are shown in blue, and those identified in both searches are shown in green. Subgroups within the clusters are highlighted for those involved in the ubiquitin pathway, and those composing CDK-cyclin complexes. Proteins highlighted in white are proteins overexpressed in cancers with oncogenic potential, while those highlighted in orange are mostly downregulated in cancers showing potential tumor suppressing activity. 8 proteins are uniquely targeted for degradation by CDC20 and 37 by CDH1, while 24 protein substrates are shared by both, for a total of 69 potential substrates. The deubiquitinase OTUD7B that deubiquitinates APC substrates was identified in both searches.

Table 1. Human APC substrates identified from BioGRID CDC20/CDH1 queries and PubMed searches of resultant hits.

CDC20 specific	CDH1 specific	shared by CDC20 and CDH1
AXIN2 [38]	BRSK2 [117]	AURKA [32, 107]
CDKN1A/p21 [38]	CCND1 [120]	AURKB [32, 108]
KIF18A [109]	CCND2 (?)	CCNA1 [32, 107]
NUP98 [110]	CCNE1 [119]	CCNA2 [32]
RASSF1 [107, 113]	CDC20 [32, 107]	CCNB1 [32, 107]
SMAR1 [114]	CDC25A[32, 107]	CCNF1 [67]
TP63 [115]	CDCA3 [32]	CDC6 [32, 107]
USP22 [116]	CDH1/FZR1 [32]	CDK1 (?) - interacts with Cyclin B1 [134]
	CDK4 [118]	CDK2 (?) - interacts with Cyclin E1 [135]
	CDK5 [121]	CLSPN [136]
	CDK6 (?) - interacts with Cyclin D1 [32]	EMI1/FBXO5 [25]
	CDKN2B (?) - interacts with CDK4/6 [122]	FBXW5 [137]
	CDR2 [80]	GMNN [32, 107]
	CKAP2 [107]	MPS1/TTK [138]
	CKS1B [32]	NEK2 [107]
	CUEDC2 (?) [85]	PAF15 [111]
	DRP1 [123]	PHF8 [139]
	E2F1 [107]	PLK1 [32, 107]
	EYA1 [32]	PTTG [32, 107]
	FMRP [108]	SKP2 [32]
	FOXM1 [32, 107]	SPRTN/DVC1 [140]
	ID1 [32, 108]	STAU1 [141]
	MOAP1 [124]	TRRAP [142]
	NEDD9 [125]
	NEDL2 [126]
	NIPA [127]
	PAX3 [128]
	PTEN [129]
	RNF157 [130]
	RRM2 [32]
	SMURF1 [131]
	SNON [132]
	TACC3 [133]
	TK1 [32, 107]
	TPX2 [32]
	USP1 [107, 112]
	USP37 [32]

Dysregulation of CDC20 or CDH1 impacts APC activity and cancer biology

Kaplan-Meier survival plots (https://kmplot.com/analysis/) of patient survival rates when either CDC20 or CDH1 are over- or underexpressed is shown in Figure 5. High level CDC20 expression is associated with poor patient survival rates, whereas high level CDH1 expression is associated with a slightly better survival rate. This is consistent with the literature suggesting that CDC20 and CDH1 interact with a distinct cohort of proteins and pathways (Figures 1–4) and have distinct roles in cell homeostasis when associated with the APC.

Figure 5. Kaplan-Meier survival plots comparing high vs low expression of the APC coactivators CDC20 and CDH1 mRNAs in breast cancer patients.

CDC20

CDC20 has been identified as being an oncogene [38]. Both overexpression and augmented protein abundance have been correlated with poor prognosis for several unrelated cancer types including brain astrocytoma [72], gastric [171], breast [49], colorectal [172], prostate [36], and pancreatic cancers [74]. A recent study found that patients with overexpression of BUB1B, CDC20, CCNA2 and CDK1 were more likely to exhibit the worst cancers [173]. Increases of CDC20 drive a dysregulated mitotic cycle in part by overwhelming the inhibitory capacity of the SAC; while the SAC is capable of blocking CDC20 function while bound to the APC, it can only simultaneously sequester 2 molecules of CDC20 at a time [154, 158]. Overaccumulation of CDC20 could forcibly activate the APC, despite an active SAC, to drive the cell through an unregulated mitotic cycle (referred to as mitotic slippage) and result in dysregulated proliferation [174, 175]. One obvious mechanism leading to CDC20 accumulation would be the dysfunction of the APC itself, resulting in inefficient CDC20 degradation. However, inhibitory mutations within Speckly-type POZ Protein (SPOP) may also result in CDC20 accumulation, as SPOP promotes the E3 ligase activity of Cullin proteins that contribute to CDC20 polyubiquitination and subsequent degradation [73]. It is thought that by driving improper APC activity (and therefore mitosis) that CDC20 primarily contributes to tumorigenesis. However, the observation that overexpression of CDC20 is accompanied by the overexpression of a host of other genes associated with APC impairment in other cancers [37], including overexpression of other APC substrates (Figure 4), indicates that it may be APC impairment, not specifically CDC20 overexpression, that is important for cancer development and/or progression, in at least some cases.

CDH1

The potential role that CDH1 plays in cell biology and tumor development is different from CDC20, as it appears to act as a tumor suppressor [42]. Loss of CDH1 activity is a common occurrence in cancer development, and the generation of heterozygous CDH1^+/- mice that are haploinsufficient incur greater rates of cancer formation [176–178]. This indicates an overall tumor suppressive function. Loss of CDH1 activity generates chromosomal abnormalities [75, 76, 176, 179], elevated sensitivity to DNA damage [180, 181], insufficient loading of Mini-Chromosome Maintenance proteins (MCMs) [75], and premature S phase entry [67, 75, 182, 183]. These abnormalities are a result of loss of key CDH1 functions when underexpressed, which include cell cycle arrest upon nutrient and genotoxic stress [16, 177, 184–186], regulation of S phase entrance [67, 164, 183], and promoting mitotic exit [187, 188]. CDH1 delays S phase progression until the cell is prepared for DNA replication by targeting proteins involved in DNA replication and S phase progression for degradation, such as Cyclin F, SKP2 (subunit of the SCF ubiquitin ligase), ORC1, CDC6 and RRM2 [32, 67]. Three activities have been reported to decrease CDH1 protein levels as cells approach S phase: APC^Cdh1 autoubiquitination [189, 190], SCF^CycF [67] and SCF^βTRCP [191]. The complicated relationship between CDH1 and cancer progression was described when suppression of CDH1 in B cell acute leukemia initially resulted in mitotic catastrophe and apoptosis, but long-term CDH1 loss contributed to development of treatment resistance [192]. It was also reported that CDH1 was found overexpressed in many malignant tumor samples, along with other APC substrates [47].

CDH1 accretion may also promote cancer development and progression. CDH1 works antagonistically with the SAC and can act to induce mitotic slippage. [193, 194]. APC^CDH1 overactivity from either CDH1 overexpression, or loss of the APC^CDH1 inhibitor, early mitotic inhibitor 1 (EMI1), may also result in DNA re-replication through the over-degradation of Geminin [195, 196]. In G2 and S phase, Geminin acts to inhibit CDT1, which is responsible for initiating DNA replication. Therefore, inappropriate loss of CDT1 inhibition may result in DNA replication occurring multiple times, triggering aneuploidy [195–197]. The wide variety of CDH1-associated activities demonstrates its complicated role in cancer progression, and warrants further investigation.

Acknowledgments

We acknowledge Dr. Chris Eskiw for careful reading of the manuscript.

Conflicts of Interest

There are no conflicts of interest to report.

Funding

Drs. Harkness and Arnason are funded by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.

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