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p53-inducible DPYSL4 associates with mitochondrial supercomplexes and regulates energy metabolism in adipocytes and cancer cells
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 115(33)
- Publication Year :
- 2018
-
Abstract
- The tumor suppressor p53 regulates multiple cellular functions, including energy metabolism. Metabolic deregulation is implicated in the pathogenesis of some cancers and in metabolic disorders and may result from the inactivation of p53 functions. Using RNA sequencing and ChIP sequencing of cancer cells and preadipocytes, we demonstrate that p53 modulates several metabolic processes via the transactivation of energy metabolism genes including dihydropyrimidinase-like 4 (DPYSL4). DPYSL4 is a member of the collapsin response mediator protein family, which is involved in cancer invasion and progression. Intriguingly, DPYSL4 overexpression in cancer cells and preadipocytes up-regulated ATP production and oxygen consumption, while DPYSL4 knockdown using siRNA or CRISPR/Cas9 down-regulated energy production. Furthermore, DPYSL4 was associated with mitochondrial supercomplexes, and deletion of its dihydropyrimidinase-like domain abolished its association and its ability to stimulate ATP production and suppress the cancer cell invasion. Mouse-xenograft and lung-metastasis models indicated that DPYSL4 expression compromised tumor growth and metastasis in vivo. Consistently, database analyses demonstrated that low DPYSL4 expression was significantly associated with poor survival of breast and ovarian cancers in accordance with its reduced expression in certain types of cancer tissues. Moreover, immunohistochemical analysis using the adipose tissue of obese patients revealed that DPYSL4 expression was positively correlated with INFg and body mass index in accordance with p53 activation. Together, these results suggest that DPYSL4 plays a key role in the tumor-suppressor function of p53 by regulating oxidative phosphorylation and the cellular energy supply via its association with mitochondrial supercomplexes, possibly linking to the pathophysiology of both cancer and obesity.
- Subjects :
- 0301 basic medicine
Male
Adipose tissue
Nerve Tissue Proteins
Oxidative phosphorylation
Mice, SCID
Biology
Metastasis
03 medical and health sciences
Transactivation
Mice
Adenosine Triphosphate
Oxygen Consumption
Cell Line, Tumor
Neoplasms
medicine
Adipocytes
Animals
Humans
Obesity
Gene knockdown
Multidisciplinary
Tumor Suppressor Proteins
Cancer
medicine.disease
ChIP-sequencing
Cell biology
Mitochondria
030104 developmental biology
Editorial
Cancer cell
Tumor Suppressor Protein p53
Energy Metabolism
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 115
- Issue :
- 33
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....f3eb664e8a2e502f5757e0f225fbf371