Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity

Abstract

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed the obese mouse phenotype. Moreover, obese human subjects showed lower expression of Par-4 relative to lean subjects, and in longitudinal studies, low baseline Par-4 levels denoted an increased risk of developing obesity later in life. These findings indicate that Par-4 suppresses p53 and its target c3 to regulate obesity.

An Atlas of Promoter Chromatin Modifications and HiChIP Regulatory Interactions in Human Subcutaneous Adipose-Derived Stem Cells

“…This cluster includes genes activated by hypoxia ( TES , STC2 , DDIT4 , SLC2A1 ), cytokine/chemokine genes ( IL33 , IL11 , CXCL5 ), and PDGFA , which is known to stimulate adipose progenitor proliferation and self-renewal but also is associated with increased adipose tissue fibrosis [ 32 , 33 ]. Cluster 4 also contains two other genes that may influence adipose tissue expansion: BAMBI , a gene known to regulate reactive oxygen levels [ 34 ] and PAWR , a suppressor of p53 [ 35 ].…”

Papel de Par-4 en tumores de cáncer de mama en etapas tardías y recurrentes

“…La obesidad juega un papel importante como factor de riesgo que reduce significativamente la sobrevida en los pacientes obesos con cáncer de Mayo 2023, Volumen 34, Número 2 https://doi.org/10.32776/revbiomed.v34i2.1106 mama se incrementa el riesgo de recurrencia del 30 al 40%, debido a que se asocia con el aumento de la supervivencia y persistencia de las células tumorales residuales (13)(14)(15)(16). En personas obesas se ha observado una menor expresión de la proteína Par-4 en comparación con los delgados; tanto en tejido adiposo como a niveles plasmáticos (17). Conforme avanza el proceso carcinogénico los factores genéticos y epigenéticos influyen en la recurrencia tumoral por la pérdida de la expresión de genes supresores de tumor como es el caso del gen Par-4 (18).…”