Aberrant Activity of Histone–Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis
Abstract
:1. Introduction
2. Structure of the KMT2 Complexes
3. Domain Structure of KMT2s
4. Substrate Specificity of KMT2 Complexes and Their Recruitment to Chromatin
5. Mutations in the KMT2 Family in Cancer
5.1. KMT2A (MLL1) and KMT2B (MLL2)
5.2. KMT2C (MLL3) and KMT2D (MLL4)
5.3. KMT2F (SET1A) and KMT2G (SET1B)
6. Roles of the Core Subunits in Oncogenesis
6.1. WDR5
6.2. RBBP5
6.3. ASH2L
6.4. DPY30
7. Therapeutic Strategies Targeting the Aberrant Activity of KMT2 Complexes in Cancers
8. Conclusions and Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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KMT2A or KMT2B Complex | KMT2C or KMT2D Complex | KMT2F or KMT2G Complex | |
---|---|---|---|
Enzyme | KMT2A or KMT2B | KMT2C or KMT2D | KMT2F or KMT2G |
Core subunits | ASH2L RBBP5 WDR5 DPY30 | ASH2L RBBP5 WDR5 DPY30 | ASH2L RBBP5 WDR5 DPY30 |
Unique subunits | Menin HCF1 or HCF2 | PTIP PA1 NCOA6 UTX | CFP1 WDR82 HCF1 |
Mode of Action | Name of Inhibitor | Cellular Outcome | Targeted Cancer Cells | References |
---|---|---|---|---|
Targeting core subunits of COMPASS: | MM-401 (microcyclic peptidomimetic) | myeloid differentiation/phenocopying KMT2A deletion | MLL-r leukemia cells in culture | [245,247] |
Antagonizing the interaction of WDR5 and KMT2A | OICR-9429 (small-molecule antagonist) | Inhibition of proliferation and induction of differentiation | Patient-derived AML cells expressing p30 | [211] |
Inhibition of cancer cell growth | Various tumor cells with a TP53 gain-of function (GOF) mutation | [154] | ||
Targeting DPY30 | Cell penetrating peptides (CPPs) derived from ASH2L | Inhibition of cancer cell growth | MLL-r leukemia cells/other MYC-dependent hematologic cancers | [287] |
Blocking interaction of Menin with KMT2A | MI-463, MI-503 (small-molecule antagonist) | Inhibition of progression of MLL leukemia in vivo vs. normal hematopoiesis | MLL-r leukemia cells/mouse model of MLL leukemia | [249] |
M-525 (small-molecule antagonist) | Suppression of MLL-regulated gene expression, leukemia cell growth inhibition | Various cell lines derived from MLL-r leukemia (MV4, MOLM-13, MOLM-14) | [250] | |
MI-2-2 (small-molecule inhibitor) | Inhibition of cell proliferation, downregulation of differentiation | MLL leukemia cells (KMT2A-F4 translocation) | [270,271] | |
Blocking interaction of KMT2A with LEDGF | CP65 (cyclic peptide) | Impairment of clonogenic growth of primary murine MLL-AF9-expressing leukemic blasts | MLL-AF9 leukemia cells | [256] |
Targeting DOT1L in KMT2A-rearranged complexes | EPZ004777 (S-adenosylmethionine-competitive inhibitor) | Downregulation of leukemic genes, inhibition of H3K79, inhibition of proliferation | Leukemia cells bearing MLL-r/extension of survival in a mouse MLL xenograft model or complete tumor regression | [237,288] |
EPZ-5676 (pinometostat) | [259] | |||
Dissociation of interacting proteins from MYC regulatory elements | I-BET (via BRD4) | Downregulation of MYC-regulated gene expression, inhibition of proliferation | Hematological cancers (MLL-r leukemia) | [242,262,289] |
A-485 (via the catalytic core of CBP/300) | Inhibition of proliferation | Lineage specific tumor cells (hematological and prostate) | [263] | |
Inhibitors of YEATS domain of AF9 and ENL (XL-13m) | Downregulation of leukemic gene drivers | MLL-r leukemia cells | [267,268] | |
Stabilization of wt KMT2A | IRAK1/4 | Inhibition of cancer cells proliferation in vitro/in vivo | MLL-r leukemia cells | [240,290] |
Restoration of normal gene expression in KMT2C mutant cells | GSK 126 (via a subunit of the polycomb repressive complex 2) | Impairment of cell proliferation, resetting the epigenetic balance of polycomb and compass function | Cells/tumors bearing mutations (PHD domain) in KMT2C | [174] |
PARP1/2-depdenent DNA repair | Olaparib (PARP1/2 inhibitor) | Synthetic lethality of cancer cells | Cancer cells with low KMT2C levels (bladder cancer) | [195] |
Pharmacologically contained glycolysis | Glycolytic inhibitors (2-deoxy-D-glucose (2-DG) | Impediment of tumorigenic growth | Lung cancer cells with KMT2D mutations | [187] |
Suppression of ADIPOR cytoplasmic signaling | AdipoRon (ADIPOR agonist) | Induction of cancer cell death through necroptosis | MIA PaCa-2 tumor cells/cancer cells isolated from patients with pancreatic cancer/TNBC cells | [206,282,283] |
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Poreba, E.; Lesniewicz, K.; Durzynska, J. Aberrant Activity of Histone–Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis. Int. J. Mol. Sci. 2020, 21, 9340. https://doi.org/10.3390/ijms21249340
Poreba E, Lesniewicz K, Durzynska J. Aberrant Activity of Histone–Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis. International Journal of Molecular Sciences. 2020; 21(24):9340. https://doi.org/10.3390/ijms21249340
Chicago/Turabian StylePoreba, Elzbieta, Krzysztof Lesniewicz, and Julia Durzynska. 2020. "Aberrant Activity of Histone–Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis" International Journal of Molecular Sciences 21, no. 24: 9340. https://doi.org/10.3390/ijms21249340