Tour d'Horizon of Recent Advances in RUNX Family Gene Research.

RUNX family transcription factors are essential regulators of diverse developmental processes, including cell proliferation, differentiation, apoptosis, and cell lineage specification (Ito et al., 2015). RUNX genes were independently identified as the fly segmentation gene Runt, a leukemia associated gene, and the subunit of a virus enhancer binding protein. Mammals possess three RUNX genes, RUNX1, RUNX2, and RUNX3, which form a heterodimeric complex in the presence of a b subunit, CBFb. Although these RUNX family members bind to the same nucleotide sequence (PuACCPuCA/TGPyGGTPy), each member has distinct tissue-specific roles (Ito et al., 2015). All are deregulated in one way or another in human diseases, indicating they are intimately involved in the pathogenesis of human disease. This special issue describes the roles of RUNX proteins in developmental processes and tumorigenesis.

The regulatory function of RUNX1 in hematopoiesis was first revealed when Runx1 was disrupted in mice (Okuda et al., 1996). RUNX1 gene disruptions caused by chromosomal translocations and mutations are frequently detected in hematological diseases, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS) (Bellissimo and Speck, 2017), indicating that RUNX1 is intimately involved in hematopoiesis and hematopoietic lineage specification and its functional dysregulation is associated with leukemia. More recent studies show that RUNX1 is also associated with various solid tumors.

The regulatory function of RUNX2 in osteogenesis was first revealed when Runx2 was disrupted in mice (Komori et al., 1997; Otto et al., 1997). Based on these studies, further work showed that human autosomal dominant bone disease cleidocranial dysplasia (CCD) is caused by RUNX2 haploinsufficiency (Lee et al., 1997; Mundlos et al., 1997; Otto et al., 1997), establishing Runx2 as a master regulator of osteogenesis. Overexpression of RUNX2 occurs in various solid tumors including osteosarcoma, lymphoma, and breast cancer, indicating that functional dysregulation of RUNX2 is associated with tumorigenesis (Blyth et al., 2006; Ferrari et al., 2013; Sadikovic et al., 2010).

Runx3 knockout mice, the result of a collaboration between my laboratory and that of Yoshiaki Ito (Li et al., 2002), cancer cell lines, and surgically dissected cancer tissues revealed that loss of RUNX3 expression occurs in, and is causally related to, gastric cancer (Li et al., 2002). RUNX3 inactivation in gastric cancer is the combined result of its hemizygous deletion and silencing by DNA hypermethylation (Li et al., 2002). Silencing of RUNX3 by DNA hypermethylation was also observed in various other cancers, suggesting that RUNX3 functions as a tumor suppressor (Ito et al., 2015). Subsequent studies revealed that RUNX3 plays key roles in suppressing not only gastric cancer but also lung cancer (Lee et al., 2013). RUNX3 also functions as an oncogene is some cancers. For example, RUNX3 is overexpressed in head and neck cancer, squamous cell carcinoma (SCC), epithelial ovarian cancer, and basal cell carcinoma (Lee et al., 2011; Salto-Tellez et al., 2006; Tsunematsu et al., 2009). In pancreatic cancer, RUNX3 functions as a tumor suppressor at the early stage and as an oncogene at the late stage of tumor progression (Whittle et al., 2015). These opposing roles of RUNX3 can be reconciled by the recent observation that RUNX3 is important for context-dependent cell fate decisions at the G1 restriction point, i.e., it determines whether cells progress through the cell cycle or enter apoptosis (Lee et al., 2019a). Therefore, RUNX3 overexpression has the potential to disturb restriction point regulation and cause unprogrammed cell proliferation in some tissues.

RUNX family members have both tumor suppressive and oncogenic activity. What makes RUNX a tumor suppressor or an oncogene? This question can only be answered after we know more about how cancers develop and how RUNX genes determine cell fate, which is critical for regulating developmental processes in diverse tissues. In this regard, it is worth mentioning that restriction point regulation, which is critical in deciding whether cells proliferate, differentiate and undergo apoptosis, is disrupted in nearly all cancer cells. Recently, all three RUNX family members were shown to be involved in restriction point regulation (Lee et al., 2019a; 2019b). It is worth emphasizing that RUNX family members bind to the same nucleotide sequence. Therefore, the results of all these studies suggest that the diverse roles of RUNX family members can be explained, at least partly, by their participation in a common cell fate decision mechanism that makes cell type-specific and context-dependent decisions.