Oncogene or Tumor Suppressor: The Coordinative Role of Lysine Methyltransferase SET7/9 in Cancer Development and the Related Mechanisms

Abstract

SET7/9 is a member of the protein lysine methyltransferase family that methylates both histone 3 lysine 4 (H3-K4) and lysine(s) of other non-histone proteins. In recent years, dis-regulation of SET7/9 were frequently detected in various cancer types and SET7/9-mediated methylation has been recognized as an important mechanism that affects cancer initiation and development through regulation of a series of cellular processes. Here we review the currently identified histone and non-histone protein targets of SET7/9 that are closely correlated with human cancer and the function of SET7/9 in regulating the expression and stability of its protein targets. The review also discusses the putative role of SET7/9 as an oncogene or tumor suppressor in the development of various cancer types and the underlying mechanisms, which may help better evaluate the potential of SET7/9 as a novel candidate for cancer therapy.

Keywords: SET7/9; cancer developments; lysine methyltransferase; methylation.

Figure 1

Schematic diagram of SET7/9. The SET7/9 protein contains an N-terminal segment and a C-terminal segment. The N-terminal helps stabilize SET7/9 protein and the C-terminal is mainly responsible for the catalytic function of SET7/9. The N-terminal contains three MORN motifs responsible for protein binding to plasma membrane phospholipids. The C-terminal contains the highly conserved SET domain. The cofactor SAM and protein substrate bind distinct sites on opposite surfaces of the SET domain.

Figure 2

Sequence alignment of a list of reported SET7/9 substrates and the recognition motifs. The asterisk indicates the targeted lysine residues methylated by SET7/9.

Figure 3

Interaction network between SET7/9 and SET7/9 substrates with experimental evidences. Protein interaction and genetic correlations are analyzed using the online tool BioGRID version 4.4 (https://thebiogrid.org/). Yellow line indicates direct physical interaction between two proteins. Green line indicates genetic interaction between two proteins. Purple line indicates both physical and genetic interaction between two proteins.

Figure 4

Regulation of p53 activity by SET7/9. On one hand, SET7/9-mediated methylation at p53 K372 stimulates subsequent acetylation and stabilization of p53. On the other hand, SET7/9 suppresses the interaction of SIRT1 and p53, thus abrogating SIRT1-mediated deacetylation of p53. The stabilized p53 protein further activates transcription of p21/WAF/CIP, induces cell apoptosis and inhibits cell proliferation.

Figure 5

The regulatory network between known SET7/9 substrates that are important transcriptional factors involved in cancer development. The action type and effects depict the type of regulation between two proteins.

Figure 6

Regulation of Wnt/β-catenin and Hippo signaling pathways by SET7/9. SET7/9 can methylate YAP K494 and β-catenin K180. Under normal conditions, methylation of β-catenin by SET7/9 promotes GSK-3β-mediated ubiquitination and degradation of the protein. Upon Hippo signaling, methylation of YAP K494 by SET7/9 binds YAP in the cytoplasm, while upon Wnt signaling activation, methylation of YAP K494 by SET7/9 leads to dissociation of the YAP-AXIN-β-catenin complex, releases β-catenin and promotes its nuclear translocation, thus facilitates Wnt/β-catenin-dependent tumorigenesis.

Figure 7

Interplay between pRb lysine methylation by SET7/9 and phosphorylation by CDK in the control of cell cycle and cell growth. (A) SET7/9 methylates pRb at K810 and hinders phosphorylation of pRb at S807 and S811 by CDK. (B) Methylation of pRb K837 is required for the repression of the E2F family transcription factors and pRb-dependent cell cycle arrest. Methylation of pRb K810 impedes phosphorylation of pRb and prevents dissociation of pRb from E2F transcription factors.

Figure 8

The regulatory network of RIOK1 by SET7/9, FBXO6, and CK2. SET7/9 methylates RIOK1 at K411. FBXO6 specifically interacts with K411-methylated RIOK1 through its FBA domain to induce RIOK1 ubiquitination. On the contrary, CK2 phosphorylates RIOK1 T410 and stabilizes the protein by antagonizing K411 methylation and impeding the interaction between FBXO6 and RIOK1.