Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Nat Genet ; 54(5): 670-683, 2022 05.
Article in English | MEDLINE | ID: mdl-35468964

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.


Subject(s)
Histone Deacetylases , Homeodomain Proteins , Lipogenesis , Prostatic Neoplasms , Androgens , Cell Line, Tumor , Epigenesis, Genetic , Histone Deacetylases/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Male , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Transcription Factors/genetics
2.
Sci Adv ; 7(15)2021 04.
Article in English | MEDLINE | ID: mdl-33827814

ABSTRACT

Forkhead box protein A1 (FOXA1) is essential for androgen-dependent prostate cancer (PCa) growth. However, how FOXA1 levels are regulated remains elusive and its therapeutic targeting proven challenging. Here, we report FOXA1 as a nonhistone substrate of enhancer of zeste homolog 2 (EZH2), which methylates FOXA1 at lysine-295. This methylation is recognized by WD40 repeat protein BUB3, which subsequently recruits ubiquitin-specific protease 7 (USP7) to remove ubiquitination and enhance FOXA1 protein stability. They functionally converge in regulating cell cycle genes and promoting PCa growth. FOXA1 is a major therapeutic target of the inhibitors of EZH2 methyltransferase activities in PCa. FOXA1-driven PCa growth can be effectively mitigated by EZH2 enzymatic inhibitors, either alone or in combination with USP7 inhibitors. Together, our study reports EZH2-catalyzed methylation as a key mechanism to FOXA1 protein stability, which may be leveraged to enhance therapeutic targeting of PCa using enzymatic EZH2 inhibitors.

3.
Am J Clin Exp Urol ; 7(2): 85-91, 2019.
Article in English | MEDLINE | ID: mdl-31139703

ABSTRACT

Polycomb group protein EZH2, a histone methyltransferase, is the enzymatic subunit of the Polycomb Repressive Complex 2 (PRC2) that catalyzes histone H3 lysine 27 methylation. They are epigenetic modifiers that mediate gene repression, or epigenetic silencing. EZH2 controls developmental regulators in embryonic stem cells and is essential for cell fate determination and transition. In the last two decades, EZH2 was reported upregulated in a variety of solid tumors, including prostate cancer, and mutated in multiple hematological malignancies, such as lymphoma. EZH2 represses the expression of a plethora of tumor suppressor genes in tumor cells, thereby promoting cell cycle, cell proliferation, and cell invasion and driving cancer progression. Recently, evidence is emerging indicating important roles of EZH2 in immune cells. Here, we review EZH2 regulation of various immune cell types, the tumor microenvironment, immune responses, and cancer immunotherapies.

SELECTION OF CITATIONS
SEARCH DETAIL
...