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HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153586 | GEO | 2022/04/01

REPOSITORIES: GEO

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HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming [RNA-Seq]

Project description:HOXB13 is a homeodomain transcription factor with prostate-specific expression. It is essential for normal prostate epithelium differentiation during development and functions as a key regulator of androgen-dependent cell growth in adult and cancerous prostate. Previous studies have demonstrated that HOXB13 is a pioneer factor of the androgen receptor (AR) and also a critical cofactor of AR variant v7 in castration-resistant prostate cancer (PCa). However, the intrinsic function of HOXB13 as a DNA-binding protein in an AR-independent context has not been elucidated. Here, our data reveal HOXB13, but not G84E mutant, recruits HDAC3 to specific genomic regions to catalyze histone de-acetylation and chromatin remodeling. We demonstrate a predominant function of HOXB13 in transcriptional repression of lipogenic genes requiring HDAC3.

2022-04-01 | GSE153585 | GEO

HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming [ChIP-Seq]

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HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming

Project description:HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming

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HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming [RNA-Seq]

Project description:HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming [RNA-Seq]

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HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming [ChIP-Seq]

Project description:HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming [ChIP-Seq]

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

Project description: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.

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Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism.

Project description:BackgroundDietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time.ResultsHere, we profile genome-wide changes in DNA methylation, gene expression and lipidomics in response to DR and aging in female mouse liver. DR is generally strongly protective against age-related changes in DNA methylation. During aging with DR, DNA methylation becomes targeted to gene bodies and is associated with reduced gene expression, particularly of genes involved in lipid metabolism. The lipid profile of the livers of DR mice is correspondingly shifted towards lowered triglyceride content and shorter chain length of triglyceride-associated fatty acids, and these effects become more pronounced with age.ConclusionsOur results indicate that DR remodels genome-wide patterns of DNA methylation so that age-related changes are profoundly delayed, while changes at loci involved in lipid metabolism affect gene expression and the resulting lipid profile.

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Caspase-10 inhibits ATP-citrate lyase-mediated metabolic and epigenetic reprogramming to suppress tumorigenesis.

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THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer

Project description:Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane-associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC.

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Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-02-03 | GSE143322 | GEO