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Reduced body size and decreased intestinal tumor rates in HDAC2-mutant mice
Stephan Zimmermann1, Franz Kiefer, Michela Prudenziati
1Institute of Toxicology, GSF National Research Center for Environment and Health, Neuherberg, Germany.
Abstract:
Histone deacetylases (HDAC) reverse the acetylation of histone and nonhistone proteins and thereby modulate chromatin structure and function of nonhistone proteins. Many tumor cell lines and experimental tumors respond to HDAC inhibition. To assess the role of an individual HDAC isoenzyme in physiology and tumor development, HDAC2-mutant mice were generated from a gene trap embryonic stem cell clone. These mice express a catalytically inactive fusion protein of the NH(2)-terminal part of HDAC2 and beta-galactosidase, which fails to integrate into corepressor complexes with mSin3B. They are the first class 1 HDAC mutant mice that are viable although they are approximately 25% smaller than their littermates. Cell number and thickness of intestinal mucosa are reduced. Mutant embryonic fibroblasts fail to respond to insulin-like growth factor I (IGF) by the IGF-I-induced increase in cell number observed in wild-type cells. These data suggest a novel link between HDACs and IGF-I-dependent responses. Crossing of HDAC2-mutant with tumor-prone APC(min) mice revealed tumor rates that are lower in HDAC2-deficient mice by 10% to 100% depending on segment of the gut and sex of the mice. These mice provide evidence that the key functions of HDAC2, although not essential for survival of the organism, play a rate-limiting role for tumor development in vivo.
Insights
Histone deacetylase 2 (HDAC2) is vital for cell growth and tumor development. HDAC2-mutant mice show reduced tumor formation, suggesting HDAC2 plays a key role in cancer progression.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Histone deacetylases (HDACs) regulate gene expression by altering protein acetylation.
- HDAC inhibition shows promise in cancer therapy, but the role of individual HDACs is unclear.
- HDAC2 is a class 1 HDAC involved in chromatin remodeling and protein function.
Purpose of the Study:
- To investigate the physiological and tumor-developmental roles of HDAC2.
- To generate and characterize HDAC2-mutant mice to study HDAC2 function in vivo.
- To explore the link between HDAC2 and insulin-like growth factor I (IGF-I) signaling.
Main Methods:
- Generation of HDAC2-mutant mice expressing a catalytically inactive HDAC2-beta-galactosidase fusion protein.
- Analysis of mouse physiology, including size, intestinal mucosa, and embryonic fibroblast response to IGF-I.
- Cross-breeding HDAC2-mutant mice with tumor-prone APC(min) mice to assess tumor development.
Main Results:
- HDAC2-mutant mice are viable but smaller, with reduced cell numbers and intestinal mucosa thickness.
- Mutant cells exhibit impaired response to IGF-I-induced cell proliferation.
- HDAC2 deficiency significantly reduces tumor rates in APC(min) mice across different gut segments and sexes.
Conclusions:
- HDAC2 is not essential for organism survival but plays a critical role in IGF-I-dependent growth.
- HDAC2 functions as a rate-limiting factor in in vivo tumor development.
- These findings highlight HDAC2 as a potential therapeutic target in cancer.
