title: Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation.
abstract: Germline mutations in the PTEN tumor-suppressor gene and germline variations in succinate dehydrogenase subunit D gene (SDHD-G12S, SDHD-H50R) are associated with a subset of Cowden syndrome and Cowden syndrome-like individuals (CS/CSL) and confer high risk of breast, thyroid and other cancers. However, very little is known about the underlying crosstalk between SDHD and PTEN in CS-associated thyroid cancer. Here, we show SDHD-G12S and SDHD-H50R lead to impaired PTEN function through alteration of its subcellular localization accompanied by resistance to apoptosis and induction of migration in both papillary and follicular thyroid carcinoma cell lines. Other studies have shown elevated proto-oncogene tyrosine kinase (SRC) activity in invasive thyroid cancer cells; so, we explore bosutinib, a specific inhibitor for SRC, to explore SRC as a mediator of SDH-PTEN crosstalk in this context. We show that SRC inhibition could rescue SDHD dysfunction-induced cellular phenotype and tumorigenesis only when wild-type PTEN is expressed, in thyroid cancer lines. Patient lymphoblast cells carrying either SDHD-G12S or SDHD-H50R also show increased nuclear PTEN and more oxidized PTEN after hydrogen peroxide treatment. Like in thyroid cells, bosutinib decreases oxidative PTEN in patient lymphoblast cells carrying SDHD variants, but not in patients carrying both SDHD variants and PTEN truncating mutations. In summary, our data suggest a novel mechanism whereby SDHD germline variants SDHD-G12S or SDHD-H50R induce thyroid tumorigenesis mediated by PTEN accumulation in the nucleus and may shed light on potential treatment with SRC inhibitors like bosutinib in PTEN-wild-type SDHD-variant/mutation positive CS/CSL patients and sporadic thyroid neoplasias.
authors.affiliation: Genomic Medicine Institute, Learner Research Institute.
authors.forename: Wanfeng
authors.initials: W
authors.lastname: Yu
authors.affiliation: Genomic Medicine Institute, Learner Research Institute.
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.affiliation: Genomic Medicine Institute, Learner Research Institute CASE Comprehensive Cancer Center Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44116, USA and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Genomic Medicine Institute, Learner Research Institute Oncology Academic Clinical Program, Duke-NUS Graduate Medical School, Singapore 169610, Singapore.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ngeow
authors.affiliation: Genomic Medicine Institute, Learner Research Institute Taussig Cancer Institute Stanley Shalom Zielony Institute of Nursing Excellence, Cleveland Clinic, Cleveland, OH 44195, USA Department of Genetics and Genome Sciences CASE Comprehensive Cancer Center Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44116, USA and engc@ccf.org.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics / Q000378:metabolism*; D000814:Aniline Compounds / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D016391:Genes, src / Q000187:drug effects; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics; D006801:Humans; D009570:Nitriles / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D000090063:Proto-Oncogene Mas; D011804:Quinolines / Q000494:pharmacology; D013385:Succinate Dehydrogenase / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; C000715470:MAS1 protein, human; D009570:Nitriles; D000090063:Proto-Oncogene Mas; D011804:Quinolines; C491545:SDHD protein, human; C471992:bosutinib; D013385:Succinate Dehydrogenase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human