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Posttranslational Modifications of RUNX1 As Potential Anticancer

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Posttranslational Modifications of RUNX1 As Potential Anticancer Oncogene (2015) 34, 3483–3492 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc REVIEW Posttranslational modifications of RUNX1 as potential anticancer targets S Goyama1, G Huang1, M Kurokawa2 and JC Mulloy1 The transcription factor RUNX1 is a master regulator of hematopoiesis. Disruption of RUNX1 activity has been implicated in the development of hematopoietic neoplasms. Recent studies also highlight the importance of RUNX1 in solid tumors both as a tumor promoter and a suppressor. Given its central role in cancer development, RUNX1 is an excellent candidate for targeted therapy. A potential strategy to target RUNX1 is through modulation of its posttranslational modifications (PTMs). Numerous studies have shown that RUNX1 activity is regulated by PTMs, including phosphorylation, acetylation, methylation and ubiquitination. These PTMs regulate RUNX1 activity either positively or negatively by altering RUNX1-mediated transcription, promoting protein degradation and affecting protein interactions. In this review, we first summarize the available data on the context- and dosage- dependent roles of RUNX1 in various types of neoplasms. We then provide a comprehensive overview of RUNX1 PTMs from biochemical and biologic perspectives. Finally, we discuss how aberrant PTMs of RUNX1 might contribute to tumorigenesis and also strategies to develop anticancer therapies targeting RUNX1 PTMs. Oncogene (2015) 34, 3483–3492; doi:10.1038/onc.2014.305; published online 29 September 2014 INTRODUCTION recent studies have revealed the important role of RUNX1 in solid 8 RUNX1 is an essential transcription factor for the generation of tumors. Given its central roles for cell fate decisions in definitive hematopoietic stem cells and for hematopoietic hematopoiesis and leukemogenesis, RUNX1 is an attractive target differentiation to myeloid and lymphoid lineages (reviewed in to develop curative therapies for leukemia patients. Such thera- Link et al.1 and Kurokawa2). RUNX1 belongs to a family of pies may also be effective against several RUNX1-dependent solid transcriptional regulators called Runx, which contain a conserved tumors. However, developing therapies for transcription factors Runt domain responsible for sequence-specific DNA binding. such as RUNX1 has been a challenge. Previous attempts to The mammalian RUNX proteins comprise three members: RUNX1, pharmacologically target RUNX1 have focused on the develop- – 9,10 RUNX2 and RUNX3. All RUNX proteins form a complex with ment of inhibitors that block RUNX1 CBFB interaction, but the cofactor CBFB. CBFB enhances the DNA-binding ability of the effects of such drugs have not been proven in clinical trials. In RUNX proteins and protects them from proteasomal degra- this review, we propose RUNX1 PTMs as alternative targets for dation, thereby increasing their function. RUNX1 also has CBFB- developing RUNX1-directed anticancer therapies. independent functions,3,4 and interacts with many other cofactors fi and chromatin modi ers, such as p300, SIN3A and histone RUNX1 IN HEMATOPOIETIC NEOPLASMS deacetylases (HDACs), to both activate and repress a broad range of hematopoietic genes. As a master regulator for hematopoiesis, RUNX1-mediated hematopoiesis has been the subject of intense RUNX1 function is tightly controlled. Several regulatory mechan- investigation. RUNX1 is involved in lineage commitment during isms exist for fine-tuning RUNX1 activity. These include alter- myeloid, B-cell and T-cell differentiation. In general, loss of RUNX1 function leads to impaired differentiation and subsequent leuke- native splicing, transcriptional control by two different promoters, 1,11 translational control and posttranslational modifications (PTMs).5,6 mia development. On the other hand, several recent studies described the survival role of RUNX1 in sustaining leukemia cell PTMs are a common strategy to regulate protein function in 12–14 diverse biologic processes. RUNX1 protein is modified by multiple growth. We here summarize context- and dosage-dependent PTMs (Figure 1). Many of these targeted residues are conserved in roles of RUNX1 in various types of hematopoietic neoplasms. RUNX2 and/or RUNX3, indicating the shared regulatory mechan- isms of PTMs for all three RUNX proteins (Figure 2; reviewed in Bae Myeloid neoplasms and Lee7). Among these modifications, phosphorylation, acetyla- The role of RUNX1 in myeloid neoplasms is well established. tion and methylation promote transcriptional activity of RUNX1. RUNX1 and its cofactor CBFB are frequent targets of chromosomal Protein stability of RUNX1 is regulated by phosphorylation and translocation in acute myeloid leukemia (AML). The chromosomal ubiquitination. These various modifications at multiple sites aberrations t(8;21) and inv(16) create RUNX1-RUNX1T1 (also called interdependently control RUNX1 function. AML1-ETO) and CBFB-MYH11 fusion genes, respectively. The AMLs Perturbation of RUNX1 function often leads to the development with RUNX1-RUNX1T1 or CBFB-MYH11 fusion genes, so-called of hematopoietic neoplasms. Beyond hematopoietic diseases, CBF-AML, are among the most common cytogenetic subtype of 1Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA and 2Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Correspondence: Dr JC Mulloy or Dr S Goyama, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, 45229 OH, USA. E-mail: [email protected] or [email protected] Received 10 July 2014; revised 13 August 2014; accepted 14 August 2014; published online 29 September 2014 PTM of RUNX1 as potential anticancer targets S Goyama et al 3484 Figure 1. PTMs of human RUNX1 (RUNX1b, NP_001001890.1). Numbers indicate positions of amino-acid residues from the N terminus. Runt domain is the DNA- and CBFB-binding domain. Activation domain is important for transcriptional activation. Ac, acetylation; APC, anaphase- promoting complex; K, lysine; Me, methylation; P, phosphorylation; R, arginine; S, serine; SCF, Skp1/Cullin/F-box protein complex; T, threonine; Ub, ubiquitination; Y, tyrosine. Figure 2. Conservation of modification residues among RUNX proteins. Sequences of RUNX proteins (human RUNX1, RUNX2 and RUNX3) were aligned using Clustal Omega (http://www.ebi.ac.uk/Tools/msa/clustalo). Many RUNX1 modification residues are conserved in either RUNX2 or RUNX3 (blue), or in both RUNX2 and RUNX3 (red). Oncogene (2015) 3483 – 3492 © 2015 Macmillan Publishers Limited PTM of RUNX1 as potential anticancer targets S Goyama et al 3485 Figure 3. Regulation of RUNX1 function in hematopoietic neoplasms. In myeloid neoplasms, RUNX1 activity is attenuated through multiple mechanisms. RUNX1-RUNX1T1, RUNX1-MECOM and CBFB-MYH11 block the function of RUNX1. MLL-fusion proteins downregulate RUNX1 expression. Genetic mutations result in loss of function of RUNX1. Although the reduced RUNX1 activity leads to myeloid maturation block and subsequent disease development, further reduction of RUNX1 activity induces cell-cycle arrest and cell death. In lymphoid neoplasms, block of RUNX1 function by ETV6-RUNX1 contributes to the development of B-ALL, and loss-of-function mutations of RUNX1 are frequently found in T-ALL. RUNX1 function is delicately controlled in t(4;11) leukemia. ALL, acute lymphoid leukemia; CMML, chronic myelomonocytic leukemia; MDS, myelodysplastic syndrome. AML, being detected in 15–20% of adult de novo AML cases.15 transplantation model for MLL-fusion leukemia, Runx1 deficiency RUNX1-MECOM (also called AML1-EVI1) is another fusion gene led to compensatory upregulation of Runx2, and combined generated by the t(3;21) translocation that retains the N-terminal deletion of Runx1/Cbfb inhibited leukemogenesis.13 Others also half of RUNX1.16 RUNX1-MECOM is found in therapy-related showed the important role of RUNX1 in CBF-AMLs. Knock-in mice myeloid neoplasms, chronic myeloid leukemia with accelerated or expressing a mutant CBFB-MYH11 lacking the RUNX1 high-affinity blastic phase and, rarely, in de novo AML. These fusion genes binding domain developed leukemia quickly despite the ineffi- disrupt the functions of RUNX1/CBFB complex. Furthermore, cient suppression of RUNX1 function by this mutant leukemia RUNX1 is mutated frequently in various types of myeloid neo- oncogene.37 Similarly, a C terminally truncated form of RUNX1- 17 plasms. Familial platelet disorder with predisposition to AML is RUNX1T1, RUNX1-RUNX1T1-9a, possesses weaker repression 18,19 caused by germline mutations in RUNX1. Somatic RUNX1 activity for RUNX1-mediated transcription but has greater mutations have been found in 15% of cytogenetically normal leukemogenic potential in a mouse bone marrow transplantation 20–22 23–26 AML, 6–11% of myelodysplastic syndromes, 10% of model.38 Furthermore, RUNX1 knockdown in Kasumi-1 and ME-1 27 chronic myelomonocytic leukemia and 20% of systemic masto- cells, which harbor RUNX1-RUNX1T1 and CBFB-MYH11, respec- 28 cytosis. These mutations commonly involve the Runt domain or tively, attenuated the cell-cycle mitotic checkpoint and induced transcription activation domain, include frameshift and nonsense 12 29,30 apoptosis. mutations and lead to loss of transcriptional activity. Thus, RUNX1 activity is attenuated in many myeloid neoplasms Functionally, RUNX1 mutants lose the
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