1. Academic Validation
  2. The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression

The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression

  • Cell Mol Biol Lett. 2021 Nov 10;26(1):45. doi: 10.1186/s11658-021-00292-7.
Weihan Li  # 1 Lei Wu  # 1 Hui Jia  # 1 2 Zenghua Lin 3 Renhao Zhong 1 2 Yukun Li 1 2 Chenwei Jiang 1 2 Shifan Liu 1 2 Xiaorong Zhou 4 Erhao Zhang 5 6
Affiliations

Affiliations

  • 1 Department of Immunology, School of Medicine, Nantong University, Nantong, 226001, People's Republic of China.
  • 2 Laboratory of Medical Science, School of Medicine, Nantong University, Nantong, 226001, People's Republic of China.
  • 3 Department of Hematology, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, People's Republic of China.
  • 4 Department of Immunology, School of Medicine, Nantong University, Nantong, 226001, People's Republic of China. zhouxiaorong@ntu.edu.cn.
  • 5 Department of Immunology, School of Medicine, Nantong University, Nantong, 226001, People's Republic of China. zhangerhao@ntu.edu.cn.
  • 6 Laboratory of Medical Science, School of Medicine, Nantong University, Nantong, 226001, People's Republic of China. zhangerhao@ntu.edu.cn.
  • # Contributed equally.
Abstract

Background: Liquid-liquid phase separation (LLPS) within the nucleus is directly linked to driving gene expression through transcriptional complexes. Histone lysine methyltransferase 2D (KMT2D) is widely present in many cancers. It is known to epigenetically stimulate the expression of genes associated with tumorigenesis and metastasis. Our analyses show that KMT2D possesses two distinct low-complexity domains (LCDs) capable of driving the assembly of membrane-less condensates. The dependence of the mechanisms underlying monomethylation of H3K4 on the LLPS microenvironment derived from KMT2D LCDs is unclear in tumor.

Methods: KMT2D LCD-depletion cells were used to investigate tumor cell proliferation, Apoptosis, and migration. We identified some core proteins, including WDR5, RBBP5, and ASH2L, which are involved in the KMT2D-associated catalytic complex in KMT2D LCD-deficient cells to further elucidate the mechanism that decreases monomethylation of H3K4. We also evaluated the viability of KMT2D LCD-deficient cells in vivo. Finally, using 1,6-hexanediol (HD), an inhibitor of LLPS, we determined cell activities associated with KMT2D function in wild-type PANC-1 cells.

Results: Without the LLPS microenvironment in KMT2D LCD-deficient cells or wild-type PANC-1 cells treated with HD, the WDR5 protein was significantly less stable and the protein-protein interactions between the components of the KMT2D-enzyme complex were attenuated, impairing the formation of the complex. Moreover, with the decrease in H3K4me1 level at enhancers, transcription factors such as LIFR and KLF4 were markedly downregulated, effectively inhibiting tumor progression. In xenograft tumor models, PANC-1 cells lacking the KMT2D LCDs showed effectively suppressed tumor growth compared to normal cells.

Conclusions: Our data indicate that the two low-complexity domains of the KMT2D protein could form a stable LLPS microenvironment, promoting the KMT2D catalysis of H3K4 monomethylation through stabilization of the WDR5 protein and KMT2D-enzyme complex. Therefore, finding ways to regulate the LLPS microenvironment will be benefitial for new Cancer treatment strategies.

Keywords

Epigenetic therapy; H3K4 monomethylation; KMT2D; Liquid–liquid phase separation; Low-complexity domain.

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