Dihydropyrimidinase-like 4 (DPYSL4), a Novel p53-Inducible Regulator of Energy Metabolism and Its Concerns in Cancer and Obesity

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 649-677-Adipocyte Biology
Basic
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-658
Hidekazu Nagano*1, Tomohiko Yoshida1, Sawako Suzuki1, Akitoshi Nakayama1, Naoko Hashimoto1, Tomoko Takiguchi1, Akina Shiga1, Seiichirou Higuchi1, Ikki Sakuma1, Hisashi Koide1, Ichiro Tatsuno2, Koutaro Yokote1 and Tomoaki Tanaka1
1Chiba University Graduate School of Medicine, Chiba, Japan, 2Toho University Sakura Medical Center, Sakura-City, Japan
Tumor suppressor p53, known as a “cellular gatekeeper”, has recently been shown to regulate energy metabolism in response to various metabolic stresses, underlying the pathogenesis of cancer as well as other aspects of disease including type 2 diabetes mellitus and obesity. In fact, p53 expression in adipose tissue was shown to be involved in the development of insulin resistance. Here we have identified DPYSL4 is a p53-inducible novel regulator of energy metabolism using RNA-seq in human preadipocytes in order to elucidate the novel metabolic function of p53. Consistent with previous reports, RNA-seq and gene ontology analysis revealed that p53 potentially modulates multiple metabolic processes through transactivation of various genes including TP53-induced glycolysis regulator (TIGAR), glutaminase2 (GLS2) and synthesis of cytochrome c oxidase (SCO2). Among them, Dihydropyrimidinase-like 4 (DPYSL4) has high homology with enzyme related to pyrimidine metabolism. Real-time PCR and ChIP-seq analysis clarified that DPYSL4 was induced in response to DNA damage in a p53-dependnent manner. We found that the overexpression of DPYSL4 upregulated ATP production and oxygen consumption, whereas its silencing downregulated energy production. Mitochondrial oxidative phosphorylation is executed by four mitochondrial protein complexes, termed as complex I-IV, for electron transfer and their supercomplex structure is known to be important for its function. Therefore, defects in these process or complex formation are tightly linked to the pathogenesis of a wide variety of human diseases including cancer, aging and diabetes. Consistent with its positive role in energy production, 2D BN/SDS PAGE revealed that DPYSL4 was associated with mitochondrial supercomplexes. Interestingly, when we examined the tissue expression of to clarify its pathophysiological role in cancer and obesity, DPYSL4 expression was reduced various cancer tissues, whereas its expression was significantly increased in human adipose tissue of obesity patients. Furthermore, overexpression of DPYSL4 suppressed the matrigel invasion of cancer cells and tumor growth after xenografts in vivo.

Thus, our results provide a role of unique p53-inducible DPYSL4, linking to the regulation of oxidative phosphorylation and energy supply through mitochondrial complex, which may contribute to the multi-functions of p53 not only in tumor suppression but also in non-cancer-associated function of p53 in obesity.

Nothing to Disclose: HN, TY, SS, AN, NH, TT, AS, SH, IS, HK, IT, KY, TT

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm