Abstract
WDR5 is a highly-conserved nuclear protein that performs multiple scaffolding functions in the context of chromatin. WDR5 is also a promising target for pharmacological inhibition in cancer, with small molecule inhibitors of an arginine-binding pocket of WDR5 (the 'WIN' site) showing efficacy against a range of cancer cell lines in vitro. Efforts to understand WDR5, or establish the mechanism of action of WIN site inhibitors, however, are stymied by its many functions in the nucleus, and a lack of knowledge of the conserved gene networks-if any-that are under its control. Here, we have performed comparative genomic analyses to identify the conserved sites of WDR5 binding to chromatin, and the conserved genes regulated by WDR5, across a diverse panel of cancer cell lines. We show that a specific cohort of protein synthesis genes (PSGs) are invariantly bound by WDR5, demonstrate that the WIN site anchors WDR5 to chromatin at these sites, and establish that PSGs are bona fide, acute, and persistent targets of WIN site blockade. Together, these data reveal that WDR5 plays a predominant transcriptional role in biomass accumulation and provide further evidence that WIN site inhibitors act to repress gene networks linked to protein synthesis homeostasis.
| Original language | English |
|---|---|
| Pages (from-to) | 2924-2941 |
| Number of pages | 18 |
| Journal | Nucleic Acids Research |
| Volume | 48 |
| Issue number | 6 |
| DOIs | |
| State | Published - Apr 6 2020 |
Bibliographical note
Publisher Copyright:© 2020 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.
Funding
National Institutes of Health [CA200709 to W.P.T., Chemical Biology Consortium Contract No. HHSN261200800001E to S.W.F., CA119925 to E.R.A., W.P.T., CA210429 to A.F.B, CA225065 to A.D.G, GM008554 to A.F.B., CA009582 to A.D.G., CA236733 to W.P.T., S.F.W., CA095103 to W.P.T.]; Robert J. Kleberg, Jr., and Helen C. Kleberg Foundation [to W.P.T. and S.W.F.]; The TJ Martell Foundation [to W.P.T. and S.W.F.]; Edward P. Evans Foundation [to W.P.T.]; Rally Foundation for Childhood Cancer Research Fellowship [to A.M.W.]; Open Hands Over?owing Hearts co-funded research fellowship [to A.M.W.]; American Association for Cancer Research Basic Cancer Research Fellowship [to A.M.W.]; The VANTAGE Shared Resource is supported by the National Institutes of Health [CA068485, EY08126, RR030956]; The Vanderbilt University Medical Center Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center [CA68485]; Vanderbilt Digestive Disease Research Center [DK058404]. Funding for open access charge: National Institutes of Health.
| Funders | Funder number |
|---|---|
| Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation | |
| Vanderbilt Digestive Disease Research Center | DK058404 |
| National Institutes of Health (NIH) | HHSN261200800001E, CA225065, GM008554, CA200709, CA095103, CA236733, CA009582, CA119925 |
| National Institutes of Health (NIH) | |
| American Association for Cancer Research | RR030956, CA068485, EY08126 |
| American Association for Cancer Research | |
| National Childhood Cancer Registry – National Cancer Institute | F31CA210429 |
| National Childhood Cancer Registry – National Cancer Institute | |
| T.J. Martell Foundation | |
| Rally Foundation | |
| Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center | |
| Vanderbilt Ingram Cancer Center | CA68485 |
| Vanderbilt Ingram Cancer Center | |
| Edward P Evans Foundation |
ASJC Scopus subject areas
- Genetics
