Abstract
HOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) activities and androgen-dependent prostate cancer (PCa) growth. However, its functions in AR-independent contexts remain elusive. Here we report HOXB13 interaction with histone deacetylase HDAC3, which is disrupted by the HOXB13 G84E mutation that has been associated with early-onset PCa. Independently of AR, HOXB13 recruits HDAC3 to lipogenic enhancers to catalyze histone deacetylation and suppress lipogenic regulators such as fatty acid synthase. Analysis of human tissues reveals that the HOXB13 gene is hypermethylated and downregulated in approximately 30% of metastatic castration-resistant PCa. HOXB13 loss or G84E mutation leads to lipid accumulation in PCa cells, thereby promoting cell motility and xenograft tumor metastasis, which is mitigated by pharmaceutical inhibition of fatty acid synthase. In summary, we present evidence that HOXB13 recruits HDAC3 to suppress de novo lipogenesis and inhibit tumor metastasis and that lipogenic pathway inhibitors may be useful to treat HOXB13-low PCa.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 670-683 |
| Number of pages | 14 |
| Journal | Nature Genetics |
| Volume | 54 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2022 |
Funding
We thank Y. Jia and W. Xie for providing some technical support for in vivo experiments. We thank all members of the Yu laboratory for helpful discussions. This work was partially supported by the Northwestern University Pathology Core Facility, the Center for Advanced Microscopy/Nikon Imaging Center and the Robert H. Lurie Comprehensive Cancer Center Support Grant (grant no. NCI P30CA060553). NGS was done at the University of Chicago Genomics Facility and lipid profiling at the Mass Spectrometry Core, University of Illinois at Chicago. IP-MS was done at the Taplin Mass Spectrometry Facility of Harvard Medical School. We thank the patients and their families, C. Higano, E. Yu, E. Mostaghel, H. Cheng, P. Nelson, B. Montgomery, M. Schweizer, A. Hsieh, J. Wright, D. Lin, F. Vakar-Lopez, X. Zhang, M. Roudier, L. True and the rapid autopsy teams for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Program and the Development of the LuCaP PDX models. Funding supports for the work include the NIH/NCI training grant no. T32CA09560 (to G.G., L.T.B.); prostate cancer SPORE grant no. P50CA180995 (to W.J.C., J.Y., X.Y.); grants no. R01CA257446 and no. R01CA227918 (to J.Y.); grant no. R50CA211271 (to J.C.Z.); NIH-R35 grant no. CA197532 (to N.S.C.); grant no. R01CA251555 (to M.L.F.); Prostate Cancer Foundation grant no. 2017CHAL2008 (to J.Y.); and the Department of Defense grants no. W81XWH-19-1-0565 and no. W81XWH-21-1-0234 (to M.L.F.) and no. W81XWH-17-1-0405 and no. W81XWH-17-1-0578 (to J.Y.). Generation and maintenance of the LuCaP PDX models were partially funded by NIH awards no. P50CA97186 and no. P01CA163227.
ASJC Scopus subject areas
- Genetics
