ArticleHuman molecular genetics2015
Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It carries an expression of concern. Cited by 20 papers.
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20 citing papers in PubMed, 28 citations in OpenAlex.
- In vivo and in vitro analysis of functional effects of the SDHD H50R variant.Endocrine-related cancer · 2025Article
- SIRT7 affects the proliferation and apoptosis of papillary thyroid cancer cells by desuccinylation of LATS1.BMC cancer · 2025Article
- Nuclear PTEN's Functions in Suppressing Tumorigenesis: Implications for Rare Cancers.Biomolecules · 2023Review
- Role of succinylation modification in thyroid cancer and breast cancer.American journal of cancer research · 2021Review
- Bayesian Gene Selection Based on Pathway Information and Network-Constrained Regularization.Computational and mathematical methods in medicine · 2021Article
- PTEN Nuclear Functions.Cold Spring Harbor perspectives in medicine · 2020Review
- PTEN in Hereditary and Sporadic Cancer.Cold Spring Harbor perspectives in medicine · 2020Review
- Review
- PTEN-opathies: from biological insights to evidence-based precision medicine.The Journal of clinical investigation · 2019Review
- CX3CL1/fractalkine enhances prostate cancer spinal metastasis by activating the Src/FAK pathway.International journal of oncology · 2018Article
- A pathogenic role for germline PTEN variants which accumulate into the nucleus.European journal of human genetics : EJHG · 2018Article
- Article
- Precancer Atlas to Drive Precision Prevention Trials.Cancer research · 2017Article
- Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells.Human molecular genetics · 2017Article
- Cancer biomarker discovery is improved by accounting for variability in general levels of drug sensitivity in pre-clinical models.Genome biology · 2016Article
- Multiple Meningiomas in a Patient with Cowden Syndrome.Journal of neurological surgery reports · 2016Article
- Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients.Hereditary cancer in clinical practice · 2016Article
- Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer.American journal of human genetics · 2015Article
- Opening the conformation is a master switch for the dual localization and phosphatase activity of PTEN.Scientific reports · 2015Article
- Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer.Endocrine-related cancer · 2015Article
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5 authors at 3 institutions in 3 countries.
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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.
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