Cowden syndrome-associated germline succinate dehydrogenase complex subunit D (SDHD) variants cause PTEN-mediated down-regulation of autophagy in thyroid cancer cells

Abstract

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.

PTEN-opathies: from biological insights to evidence-based precision medicine

“…Importantly, the selective SRC inhibitor bosutinib could rescue these tumorigenic phenotypes only when wild-type PTEN was present. Similarly, SDHD p.G12S and p.H50R variants result in reduced autophagy in a PTEN-dependent manner (98). From a clinical perspective, these data provide mechanistic insights that could explain the increased prevalence of thyroid cancer in CS patients with SDHx variants alone compared with those with PTEN mutations alone, as well as the seemingly paradoxical decreased prevalence of thyroid cancer in the setting of coexisting PTEN mutations and SDHx variants.…”

Mulberry anthocyanins improves thyroid cancer progression mainly by inducing apoptosis and autophagy cell death

“…Thyroid cancer incidence is very high, and it is the most common malignant tumor in the endocrine system [8,9]. There are four main types of thyroid carcinoma: papillary thyroid carcinoma, medullary carcinoma, undifferentiated carcinoma and follicular thyroid carcinoma [10].…”

PTEN in Hereditary and Sporadic Cancer

“…Importantly, the specific SRC inhibitor bosutinib could rescue these tumorigenic phenotypes only when wild-type PTEN was present. Similarly, SDHD p.G12S and p.H50R variants result in reduced autophagy in a PTEN-dependent manner (Yu et al 2017). These data indeed provide mechanistic insights regarding the clinically observed increased prevalence of thyroid cancer in CS patients with SDHx variants alone compared to those with PTEN mutations alone, yet the seemingly paradoxical decreased prevalence of thyroid cancer in the setting of coexisting PTEN mutations and SDHx variants.…”