Abstract
Cell migration is a critical requirement for cancer metastasis. Cytokine production and its role in cancer cell migration have been traditionally associated with immune cells in the tumor microenvironment. MLL1 is a histone methyltransferase that controls 3D cell migration via the secretion of cytokines, IL-6 and TGF-β1, by the cancer cells themselves. In vivo, MLL1 depletion reduced metastatic burden and prolonged survival. MLL1 exerts its effects with its scaffold protein, Menin. Mechanistically, the MLL1-Menin interaction controls actin filament assembly via the IL-6/pSTAT3/Arp3 axis and acto-myosin contractility via the TGF-β1/Gli2/ROCK1/2/pMLC2 axis, which regulate dynamic protrusion generation and 3D cell migration. MLL1 also regulates cell proliferation via mitosis-based and cell cycle-related pathways. Combining an MLL1-Menin inhibitor with Paclitaxel, a standard chemotherapeutic, abrogated tumor growth and metastasis in a syngeneic model. These results highlight the potential of targeting the MLL1 in metastasis prevention and its potential to be combined with currently administered chemotherapeutics.
Statement of Significance We identify MLL1 as being vital to metastasis, which causes the vast majority of cancer-related deaths. MLL1 controls cell migration, a requirement for metastasis, by regulating the secretion of cytokines. MLL1 inhibition lowers metastatic burden independent of its impact on primary tumor growth, highlighting its anti-metastatic potential in TNBC.
Competing Interest Statement
One of the authors, R.F., is a shareholder in AtlasXomics. All other authors declare no competing interests.
Acronyms
- CM
- Conditioned medium
- EMT
- Epithelial to mesenchymal transition
- GSEA
- Gene Set Enrichment Analysis
- H3K4
- Histone 3 Lysine (K) 4
- HD
- High density (100 cells/mm3)
- HR
- Hazard Ratio
- IL
- Interleukin
- LD
- Low density (10 cells/mm3)
- MLC
- Myosin Light Chain
- ND
- Not detected
- pMLC2
- phospho-Myosin Light Chain 2
- MLL1
- Mixed Lineage Leukemia
- MLL i
- MLL1-Menin interaction inhibitor/inhibition
- MSD
- Mean squared displacement
- SC
- (Non-targeting) Scrambled shRNA Control
- TCGA
- The Cancer Genome Atlas
- TGF
- Transforming Growth Factor
- TCGA
- The Cancer Genome Atlas
- TNBC
- Triple negative breast cancer
- TSS
- Transcription start site
- WT
- Wild-type
