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Modulation of cell adhesion and migration by the histone methyltransferase subunit mDpy-30 and its interacting
Bin Xia1, Alexandra Joubert, Benjamin Groves
1Department of Pediatrics, Sichuan University, West China Second University Hospital, Chengdu, China.
Abstract:
We have previously shown that a subset of mDpy-30, an accessory subunit of the nuclear histone H3 lysine 4 methyltransferase (H3K4MT) complex, also localizes at the trans-Golgi network (TGN), where its recruitment is mediated by the TGN-localized ARF guanine nucleotide exchange factor (ArfGEF) BIG1. Depletion of mDpy-30 inhibits the endosome-to-TGN transport of internalized CIMPR receptors and concurrently promotes their accumulation at the cell protrusion. These observations suggest mDpy-30 may play a novel role at the crossroads of endosomal trafficking, nuclear transcription and adhesion/migration. Here we provide novel mechanistic and functional insight into this association. First, we demonstrate a direct interaction between mDpy-30 and BIG1 and locate the binding region in the N-terminus of BIG1. Second, we provide evidence that the depletion or overexpression of mDpy-30 enhances or inhibits cellular adhesion/migration of glioma cells in vitro, respectively. A similar increase in cell adhesion/migration is observed in cells with reduced levels of BIG1 or other H3K4MT subunits. Third, knockdown of mDpy-30, BIG1, or the RbBP5 H3K4MT subunit increases the targeting of beta1 integrin to cell protrusions, and suppression of H3K4MT activity by depleting mDpy-30 or RbBP5 leads to increased protein and mRNA levels of beta1 integrin. Moreover, stimulation of cell adhesion/migration via mDpy-30 knockdown is abolished after treating cells with a function-blocking antibody to beta1 integrin. Taken together, these data indicate that mDpy-30 and its interacting proteins function as a novel class of cellular adhesion/migration modulators partially by affecting the subcellular distribution of endosomal compartments as well as the expression of key adhesion/migration proteins such as beta1 integrin.
Insights
The histone methyltransferase subunit mDpy-30 modulates glioma cell adhesion and migration by interacting with BIG1 and influencing beta1 integrin levels and localization.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- The histone H3 lysine 4 methyltransferase (H3K4MT) complex subunit mDpy-30 is known to localize to the nucleus and the trans-Golgi network (TGN).
- Recruitment of mDpy-30 to the TGN is mediated by the Arf guanine nucleotide exchange factor (ArfGEF) BIG1.
- mDpy-30 depletion disrupts endosome-to-TGN transport and causes receptor accumulation at cell protrusions, suggesting roles in trafficking, transcription, and cell migration.
Purpose of the Study:
- To elucidate the mechanistic and functional roles of mDpy-30 in cellular adhesion and migration.
- To investigate the interaction between mDpy-30 and BIG1.
- To determine the impact of mDpy-30 and related proteins on beta1 integrin expression and localization.
Main Methods:
- Co-immunoprecipitation to demonstrate direct interaction between mDpy-30 and BIG1.
- In vitro cell adhesion and migration assays using glioma cells with altered mDpy-30, BIG1, or RbBP5 levels.
- Western blotting and RT-qPCR to assess beta1 integrin protein and mRNA levels.
- Immunofluorescence microscopy to analyze beta1 integrin localization.
- Functional blocking antibody treatment to inhibit beta1 integrin activity.
Main Results:
- A direct interaction between mDpy-30 and BIG1 was confirmed, with the binding site located in BIG1's N-terminus.
- mDpy-30 depletion enhanced glioma cell adhesion/migration, while overexpression inhibited it; similar effects were seen with reduced BIG1 or other H3K4MT subunits.
- Knockdown of mDpy-30, BIG1, or RbBP5 increased beta1 integrin targeting to cell protrusions.
- Suppression of H3K4MT activity led to increased beta1 integrin expression.
- Blocking beta1 integrin function abolished the enhanced cell adhesion/migration observed upon mDpy-30 knockdown.
Conclusions:
- mDpy-30 and its interacting proteins (BIG1, RbBP5) represent a novel class of modulators for cellular adhesion and migration.
- These proteins influence cell migration by altering endosomal compartment distribution and regulating the expression of key adhesion molecules like beta1 integrin.
- The findings highlight a significant role for epigenetic regulators in controlling cell motility and potentially cancer progression.
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