Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors

English version

Autoři: Joe R. Delaney ^aff001; Chandni B. Patel ^aff001; Jaidev Bapat ^aff001; Christian M. Jones ^aff004; Maria Ramos-Zapatero ^aff001; Katherine K. Ortell ^aff004; Ralph Tanios ^aff004; Mina Haghighiabyaneh ^aff001; Joshua Axelrod ^aff001; John W. DeStefano ^aff004; Isabelle Tancioni ^aff001; David D. Schlaepfer ^aff001; Olivier Harismendy ^aff001; Albert R. La Spada ^aff003; Dwayne G. Stupack ^aff001
Působiště autorů: UC San Diego Moores Cancer Center, La Jolla, California, United States of America ^aff001; Department of Obstetrics, Gynecology, and Reproductive Sciences, UC San Diego School of Medicine, La Jolla, California, United States of America ^aff002; Departments of Neurology, Neurobiology, and Cell Biology, and the Duke Center for Neurodegeneration & Neurotherapeutics, Duke University School of Medicine, Durham, North Carolina, United States of America ^aff003; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America ^aff004; Department of Pediatrics and Division of Biological Sciences, UC San Diego School of Medicine, La Jolla, California, United States of America ^aff005; Division of Biomedical Informatics, Department of Medicine, UC San Diego School of Medicine, La Jolla, California, United States of America ^aff006
Vyšlo v časopise: Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors. PLoS Genet 16(1): e1008558. doi:10.1371/journal.pgen.1008558
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008558

Souhrn

Autophagy, particularly with BECN1, has paradoxically been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, studying the specific role of BECN1 at the genetic level is complicated due to its genomic proximity to BRCA1 on both human (chromosome 17) and murine (chromosome 11) genomes. In human breast and ovarian cancers, the monoallelic deletion of these genes is often co-occurring. To investigate the potential tumor suppressor roles of two of the most commonly deleted autophagy genes in ovarian cancer, BECN1 and MAP1LC3B were knocked-down in atypical (BECN1+/+ and MAP1LC3B+/+) ovarian cancer cells. Ultra-performance liquid chromatography mass-spectrometry metabolomics revealed reduced levels of acetyl-CoA which corresponded with elevated levels of glycerophospholipids and sphingolipids. Migration rates of ovarian cancer cells were increased upon autophagy gene knockdown. Genomic instability was increased, resulting in copy-number alteration patterns which mimicked high grade serous ovarian cancer. We further investigated the causal role of Becn1 haploinsufficiency for oncogenesis in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Tumors were evident earlier among the Becn1+/- mice, and this correlated with an increase in copy-number alterations per chromosome in the Becn1+/- tumors. The results support monoallelic loss of BECN1 as permissive for tumor initiation and potentiating for genomic instability in ovarian cancer.

Klíčová slova:

Autophagic cell death – Genetic causes of cancer – Genetic networks – Chromosome structure and function – Mammalian genomics – Mouse models – Ovarian cancer – Tumor suppressor genes

Zdroje

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