HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming in prostate cancer

• Published in: Nature genetics Vol. 54; no. 5; pp. 670 - 683
• Main Authors: Lu, Xiaodong, Fong, Ka-wing, Gritsina, Galina, Wang, Fang, Baca, Sylvan C., Brea, Lourdes T., Berchuck, Jacob E., Spisak, Sandor, Ross, Jenny, Morrissey, Colm, Corey, Eva, Chandel, Navdeep S., Catalona, William J., Yang, Ximing, Freedman, Matthew L., Zhao, Jonathan C., Yu, Jindan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2022; Nature Publishing Group
• Subjects: 631/208/177; 631/67/1059/602; 692/699/67/589/466; Age; Agriculture; Androgen receptors; Androgens; Animal Genetics and Genomics; Binding sites; Biomedical and Life Sciences; Biomedicine; Biosynthesis; Cancer Research; Castration; Cell cycle; Cell division; Cell Line, Tumor; Deacetylation; Enhancers; Enzymes; Epigenesis, Genetic; Epigenetics; Fatty acids; Fatty-acid synthase; Gene expression; Gene Function; Genomes; Histone deacetylase; Histone Deacetylases - metabolism; Histones; Homeobox; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Hoxb13 gene; Human Genetics; Human tissues; Humans; Kinases; Lipids; Lipogenesis; Male; Metabolism; Metastases; Metastasis; Motility; Mutation; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Roles; Sterols; Transcription Factors - genetics; Tumorigenesis; Tumors; Xenografts; Xenotransplantation
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-022-01045-8

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. HOXB13 suppresses a lipogenic transcriptional program in prostate cancer (PCa) through HDAC3 recruitment to enhancers. Loss of HOXB13 leads to lipid accumulation in PCa cells, promoting cell motility in vitro and xenograft tumor metastasis in vivo.