Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity

Nathalia Araujo, James Sledziona, Sunil K. Noothi, Ravshan Burikhanov, Nikhil Hebbar, Saptadwipa Ganguly, Tripti Shrestha-Bhattarai, Beibei Zhu, Wendy S. Katz, Yi Zhang, Barry S. Taylor, Jinze Liu, Li Chen, Heidi L. Weiss, Daheng He, Chi Wang, Andrew J. Morris, Lisa A. Cassis, Mariana Nikolova-Karakashian, Prabhakar R. NagareddyOlle Melander, B. Mark Evers, Philip A. Kern, Vivek M. Rangnekar

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number860446
JournalFrontiers in Oncology
Volume12
DOIs
StatePublished - Mar 29 2022

Bibliographical note

Funding Information:
This work was supported by NIH/NCI grants R01 CA165469, R01 CA187273, and R21 CA179283 (to VR), along with R01 DK071349 and DK080327, and CTSA grant UL1 TR001998 (to PK), and R01 DK112034 (to BE). NA was supported by a scholarship (ID 13137-13-1) from Coordenação de Aperfeiçoamento Superior (CAPES), Brazil. JS was supported by NCI grant T32 CA165990 (to VR).

Funding Information:
We thank Nidhi Shukla and Yanming Zhao for assistance with mouse experiments, Yuanyuan Wu for assistance with RNA-Seq analysis, and Dr. Nancy Webb, University of Kentucky, for critical reading of the manuscript. This research was also supported by Energy Balance and Body Composition Core of the University of Kentucky Center of Research in Obesity and Cardiovascular Disease and the University of Kentucky CCTS Biospecimen Core, and the following University of Kentucky Markey Cancer Center Shared Resource Facilities (P30 CA177558): Biospecimen Procurement and Translational Pathology, Biostatistics and Bioinformatics, and Cancer Research Informatics. The University of Kentucky Markey Cancer Center’s Research Communications Office assisted with preparation of the manuscript.

Publisher Copyright:
Copyright © 2022 Araujo, Sledziona, Noothi, Burikhanov, Hebbar, Ganguly, Shrestha-Bhattarai, Zhu, Katz, Zhang, Taylor, Liu, Chen, Weiss, He, Wang, Morris, Cassis, Nikolova-Karakashian, Nagareddy, Melander, Evers, Kern and Rangnekar.

Keywords

  • C3
  • Par-4
  • acylation stimulating protein
  • adipocyte tissue storage
  • fat absorption
  • hypertrophic obesity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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