Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment

Moskovich, Dotan; Finkelshtein, Yael; Alfandari, Adi; Rosemarin, Amit; Lifschytz, Tzuri; Weisz, Avivit; Mondal, Santanu; Ungati, Harinarayana; Katzav, Aviva; Kidron, Debora; Mugesh, Govindasamy; Ellis, Martin; Lerer, Bernard; Ashur‐Fabian, Osnat

doi:10.1038/s41388-021-02020-z

Cited by 8 publications

(2 citation statements)

References 49 publications

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“…DIO3 (Iodothyronine Deiodinase 3) plays a major role during embryogenesis and has also been described to promote cancer development by inhibiting tumor-suppressive actions of thyroid hormone T3 in several malignancies such as ovarian [26], lung [25], or prostate [13] cancer. Given the lack of a sufficient antibody for immunohistochemistry, we analyzed the expression in our series by RT-PCR.…”

Section: Discussionmentioning

confidence: 99%

Expression of decitabine-targeted oncogenes in meningiomas in vivo

et al. 2022

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Treatment of meningiomas refractory to surgery and irradiation is challenging and effective chemotherapies are still lacking. Recently, in vitro analyses revealed decitabine (DCT, 5-aza-2’–deoxycytidine) to be effective in high-grade meningiomas and, moreover, to induce hypomethylation of distinct oncogenes only sparsely described in meningiomas in vivo yet.Expression of the corresponding onco- and tumor suppressor genes TRIM58, FAM84B, ELOVL2, MAL2, LMO3, and DIO3 were analyzed and scored by immunohistochemical staining and RT-PCR in samples of 111 meningioma patients. Correlations with clinical and histological variables and prognosis were analyzed in uni- and multivariate analyses.All analyzed oncogenes were highly expressed in meningiomas. Expression scores of TRIM58 tended to be higher in benign than in high-grade tumors 20 vs 16 (p = .002) and all 9 samples lacking TRIM58 expression displayed WHO grade II/III histology. In contrast, median expression scores for both FAM84B (6 vs 4, p ≤ .001) and ELOVL2 (9 vs 6, p < .001) were increased in high-grade as compared to benign meningiomas. DIO3 expression was distinctly higher in all analyzed samples as compared to the reference decitabine-resistant Ben-Men 1 cell line. Increased ELOVL2 expression (score ≥ 8) correlated with tumor relapse in both uni- (HR: 2.42, 95%CI 1.18–4.94; p = .015) and multivariate (HR: 2.09, 95%CI 1.01–4.44; p = .046) analyses.All oncogenes involved in DCT efficacy in vitro are also widely expressed in vivo, and expression is partially associated with histology and prognosis. These results strongly encourage further analyses of DCT efficiency in meningiomas in vitro and in situ.

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Section: Discussionmentioning

confidence: 99%

Expression of decitabine-targeted oncogenes in meningiomas in vivo

et al. 2022

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“…This work by Manka and coworkers provides the conceptual framework to develop novel isotype‐ and cell type‐specific or liver‐directed therapies targeting TRα activities in HSCs. In addition, future research may also address therapeutic strategies modulating the hepatic TH availability beyond addressing TRs directly, for example, via specific targeting TH metabolizing enzymes such as Dio1 or TH transporters molecules such as MCT8 6,19,20 …”

Section: Figurementioning

confidence: 99%

Cell type‐specific actions of thyroid hormones in nonalcoholic steatohepatitis and liver fibrosis

Puengel,

Tacke

2024

Liver International

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The selenoenzyme type I iodothyronine deiodinase: a new tumor suppressor in ovarian cancer

Alfandari,

Moskovich,

Weisz

et al. 2024

Molecular Oncology

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The selenoenzyme type I iodothyronine deiodinase (DIO1) catalyzes removal of iodine atoms from thyroid hormones. Although DIO1 action is reported to be disturbed in several malignancies, no work has been conducted in high‐grade serous ovarian carcinoma (HGSOC), the most lethal gynecologic cancer. We studied DIO1 expression in HGSOC patients [The Cancer Genome Atlas (TCGA) data and tumor tissues], human cell lines (ES‐2 and Kuramochi), normal Chinese hamster ovarian cells (CHO‐K1), and normal human fallopian tube cells (FT282 and FT109). To study its functional role, DIO1 was overexpressed, inhibited [by propylthiouracil (PTU)], or knocked down (KD), and cell count, proliferation, apoptosis, cell viability, and proteomics analysis were performed. Lower DIO1 levels were observed in HGSOC compared to normal cells and tissues. TCGA analyses confirmed that low DIO1 mRNA expression correlated with worse survival and therapy resistance in patients. Silencing or inhibiting the enzyme led to enhanced ovarian cancer proliferation, while an opposite effect was shown following DIO1 ectopic expression. Proteomics analysis in DIO1‐KD cells revealed global changes in proteins that facilitate tumor metabolism and progression. In conclusion, DIO1 expression and ovarian cancer progression are inversely correlated, highlighting a tumor suppressive role for this enzyme and its potential use as a biomarker in this disease.

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Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment

Cited by 8 publications

References 49 publications

Expression of decitabine-targeted oncogenes in meningiomas in vivo

Expression of decitabine-targeted oncogenes in meningiomas in vivo

Cell type‐specific actions of thyroid hormones in nonalcoholic steatohepatitis and liver fibrosis

The selenoenzyme type I iodothyronine deiodinase: a new tumor suppressor in ovarian cancer

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