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Adipocyte p62/SQSTM1 suppresses tumorigenesis through the opposite regulation of metabolism in fat and tumor

ABSTRACT: Obesity is a leading risk factor for tumorigenesis and there is emerging support for a positive association between obesity and a more aggressive fatal prostate cancer. However, a complete understanding of the specific cross-talk between adipocytes and tumor cells in vivo and independently of dietary contributions is a major gap in the field. Here we interrogated human cancer data sets and used a TRAMP+ mouse line in which the signaling adaptor p62/Sqstm1is selectively inactivated in the adipose tissue. Our data demonstrate that p62 loss in adipocytes promotes an aggressive metastatic prostate cancer (PCa) phenotype with marked enrichment in fatty acid oxidation genes. Reciprocally, p62-deficiency in adipocytes promotes a general shutdown of energy utilizing pathways through mTORC1 inhibition trigger by the tumor in vivo. This reveals a central role of adipose p62 in the symbiotic adipocyte-tumor collaboration to promote the tumor metabolic fitness by enhancing its metabolism at expenses of that of the adipocyte.

ORGANISM(S): Mus musculus

PROVIDER: GSE100060 | GEO | 2019/06/26

REPOSITORIES: GEO

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Project description:Aims: Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of Heart and neural crest derivatives-expressed protein 2 (HAND2) in adipogenesis. Methods: Human white adipose tissue (WAT) were collected in a cross-sectional study of 318 individuals. In vitro, for mechanistic experiments we used primary adipocytes from human and mice as well as human multipotent adipose derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary adipocytes from LoxP mouse models with Cre-encoding mRNA. Adipogenesis efficiency was measured by OilRedO staining, qPCR and microarray. A combinatorial RNASeq approach was used to identify gene clusters regulated by HAND2. In vivo, we created a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (HAND2AdipoqCRE). Results: We found that HAND2 is an obesity-linked white adipocyte transcription factor regulated by glucocorticoids that was required but insufficient for adipocyte differentiation in vitro. In a large cohort of humans with obesity, WAT HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes compared to brown, induced early in differentiation and responded to DEX, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by GCs via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. Conclusion: In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.

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Adipocyte p62/SQSTM1 suppresses tumorigenesis through the opposite regulation of metabolism in fat and tumor

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