Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells.
Thyroid cancer is a major component cancer of Cowden syndrome (CS), a disorder typically associated with germline mutations in PTEN. Germline variants in succinate dehydrogenase genes (SDHx) co-occurring with PTEN germline mutations confer a 2-fold increased prevalence (OR 2.7) of thyroid cancer compared to PTEN-associated CS but 50% decreased prevalence (OR 0.54) of thyroid cancer compared to SDHx-associated CS. We have previously shown that CS-associated SDHD variants G12S and H50R induce PTEN oxidation and nuclear accumulation in thyroid cancer. Our current study shows that SDHD-G12S and -H50R variants cause down-regulation of autophagy, demonstrating a role for SDHD in autophagy-associated pathogenesis of differentiated thyroid cancer. These findings could explain the increased prevalence of thyroid cancer in CS patients with SDHx germline mutations compared to those with PTEN mutations alone. Importantly, we demonstrate the dependence of this process on functional wild-type PTEN with reversal of decreased autophagy after PTEN knockdown. The latter could explain the clinically observed decrease in thyroid cancer prevalence in patients with co-existent PTEN mutations and SDHx variants. We also show that SDHD-G12S/H50R promotes mono-ubiquitination of PTEN, causing its translocation into the nucleus, upregulation of AKT and consequent phosphorylation of FOXO3a. Furthermore, SDHD-G12S/H50R-mediated increase in acetylation of FOXO3a further enhances AKT-associated phosphorylation of FOXO3a. This combination of phosphorylation and acetylation of FOXO3a results in its nuclear export for degradation and consequent down-regulation of FOXO3a-target autophagy-related gene (ATG) expression. Overall, our study reveals a novel mechanism of crosstalk amongst SDHD, PTEN and autophagy pathways and their potential roles in thyroid carcinogenesis.
Genomic Medicine Institute.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Wanfeng
W
Yu
Genomic Medicine Institute.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Ying
Y
Ni
Division of Endocrinology and Metabolism, Department of Internal Medicine.|Molecular Biology and Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Motoyasu
M
Saji
Division of Endocrinology and Metabolism, Department of Internal Medicine.|Molecular Biology and Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Matthew D
MD
Ringel
Genomic Medicine Institute.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.|Germline High Risk Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Ritika
R
Jaini
Genomic Medicine Institute.|Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.|Germline High Risk Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.|Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.|Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Charis
C
Eng
D001343:Autophagy / Q000235:genetics; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D000071316:Forkhead Box Protein O3 / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation / Q000235:genetics; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D047908:Intracellular Signaling Peptides and Proteins; C491545:SDHD protein, human; D013385:Succinate Dehydrogenase; D000071189:Autophagy-Related Protein-1 Homolog; D051058:Oncogene Protein v-akt; C484754:ULK1 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human