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

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.

Quercetin as a JAK–STAT inhibitor: a potential role in solid tumors and neurodegenerative diseases

“…Pancreatic cancer (PC), a highly fatal disease, is one of the most commonly occurring digestive malignancies. PC is one of the leading causes of cancer-related death worldwide [ 53 , 74 , 75 ]. Moreover, patients with PC have a 5-year survival rate of 21.3% for local-stage cancer, 8.9% for regional-stage cancer, and 1.8% for distant-stage cancer [ 76 ].…”

Macular dystrophy in Kabuki syndrome due to de novo KMT2D variants: refining the phenotype with multimodal imaging and follow-up over 10 years: insight into pathophysiology

“…It also possesses 7 plant homeostatic domains (PHDs) that recognize H4 histone tails, which allows for spatial guidance of the KMT2D catalytic SET domain to H3 histone tails (Fig. 4 A) [ 21 , 22 ]. In addition to its active enzymatic-role, KMT2D serves as a scaffold protein forming the core nuclear regulatory machinery known as the KMT2C/D COMPASS complexes (complex of proteins associating with Set1) [ 23 ].…”

“…In the complex, histone modification-associated proteins, such as WRAD (WDR5, RbBP5, ASH2L, and DPY30) and UTX, are hosted by the low-complexity regions and interaction motifs in KMT2D (e.g., high mobility group [HMG-I] domain and nuclear receptor interacting motifs [LXXLLs]) (Fig. 4 A) [ 21 , 23 ].

Fig.

…”

Successful immunotherapy with PD-1 Iinhibitor for advanced pancreatic cancer: report of two cases and review of literature

“…The KMT2D gene encodes a histone lysine methyltransferase 2D which belongs to the mammalian histone H3 lysine 4 (H3K4) methyltransferase family and plays an important role in regulating growth, development, differentiation and metabolism [42]. KMT2D mutations are found in various types of cancer, including pancreatic cancer [43]. The missense mutation in exon 10 of the KMT2D gene was identified in our case 2.…”