Kexin Xu
University of Virginia, VA·Biochemistry
Before a gene's message can be used to build a protein, its mRNA (messenger RNA) must leave the nucleus. It exits through nuclear pore complexes, channels in the nuclear envelope.
- Fields
Biochemistry
Genetics
Pharmacology
- Topics
m6A
N6-methyladenosine
RNA methylation
- Grants
- 3 known grants, through Jan 2029
What they work on
- Examine how the m6A-adding enzyme METTL3 binds the nuclear pore protein NUP93 to speed export of m6A-marked mRNAs, using single-molecule microscopy and epitranscriptome-editing tools.
- Determine which transcripts depend on the METTL3-NUP93 axis for export, and why the pathway matters biologically, including how NUP93 mutations linked to steroid-resistant nephrotic syndrome disrupt it.
- Determine how the METTL3-NUP93 complex exports mRNAs for androgen-making enzymes, raising androgen levels inside tumors and activating the androgen receptor in castration-resistant prostate cancer.
- Test genetic and drug strategies that block METTL3-NUP93-mediated mRNA export as treatments for castration-resistant prostate cancer, using cell and animal models.
- Develop small molecules that bind the N-terminal transactivation domain of EZH2, a gene-activating region separate from its enzyme domain, by studying structure-activity relationships and modeling binding to a lead compound.
- Evaluate the pharmacokinetics, efficacy and mechanism of new EZH2 inhibitors in estrogen receptor-negative breast cancer cells and xenograft mice, using RNA-seq, ChIP-seq and proteomics.
More about the research
Cells can tag mRNAs with chemical marks that affect where they go. One such mark is m6A, a methyl group added to the base adenosine. These projects ask how this tagging and transport system works, and how cancer cells misuse it and related gene-control proteins. Two projects follow a new mRNA export route, from basic mechanism to its role in prostate cancer. A third aims to develop a new kind of drug against an epigenetic cancer protein in breast cancer.
Why it matters
Castration-resistant prostate cancer and estrogen receptor-negative breast cancer are aggressive cancers with limited treatment options. This work could yield new drug targets, such as the METTL3-NUP93 mRNA export pathway, and a first-in-class EZH2 inhibitor for tumors that do not respond to current EZH2 drugs. Understanding NUP93 mutations may also inform treatments for kidney disease caused by these mutations.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Function of the METTL3-NUP93 complex-mediated nuclear export of m6A-modified mRNAs in castration-resistant prostate cancer.
NIH · Apr 2023 – Jan 2029
METTL3-NUP93 interaction facilitates the nuclear export of m6A-modified mRNAs
NIH · Aug 2021 – Jul 2027
Development of a new class of EZH2 inhibitors in ERa-negative breast cancer
NIH · Sep 2024 – May 2027
Closest labs
Feng Yang
Baylor College of Medicine, TX·Medicine & Clinical Research
Determine how COP1, an E3 ubiquitin ligase, binds and tags GATA2 for degradation in prostate cancer cells, including castration-resistant and taxane-resistant models.
Yunsun Nam
University of Texas Southwestern Medical Center, TX·Biochemistry
Determine how heavy metals alter the efficiency and specificity of METTL3-METTL14, the enzyme that adds m6A marks to mRNA, and how metal-driven m6A changes link to chromatin and DNA methylation.
Susan Logan
New York University, NY·Pharmacology
Test whether macrocycle 13, a synthetic ring-shaped molecule designed to block beta-catenin from binding its DNA partner TCF, suppresses Wnt/beta-catenin signaling in in vivo models of castration-resistant prostate cancer.
The school
University of Virginia: 43 labs on PI Pages, $814M a year on research, 413 research doctorates a year.
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