The SUMO specific peptidase SENP3 promotes papillary thyroid cancer progression by deSUMOylation of SETDB1 and regulating GLI2 transcription

Sep 23, 2026

Uploaded by Franzy

SUMO-specific protease 3 (SENP3) is investigated in papillary thyroid cancer (PTC), where its role in carcinogenesis had not been defined. SENP3 protein is upregulated in PTC tissues and cell lines, and functional assays using K-1 cells show that SENP3 overexpression promotes proliferation and invasion while inducing G0/G1 arrest and inhibiting apoptosis; knockdown reverses these effects. Mechanistically, SENP3-dependent deSUMOylation enables SETDB1 to repress GLI2 transcription via H3K9 trimethylation, and GLI2 overexpression or XL147 targets modulate SENP3-driven phenotypes. In vivo, SENP3 knockdown reduces xenograft tumor growth. This work supports SENP3 as a potential therapeutic target for PTC.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

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Introduction

Background on thyroid cancer and PTC progression

Overview of SUMOylation and SENPs

Rationale for studying SENP3

Clinical and Experimental Medicine (2026) 26:237 [https://doi.org/10.1007/s10238-026-02151-1](https://doi.org/10.1007/s10238-026-02151-1) RESEARCH The SUMO specific peptidase SENP3 promotes papillary thyroid cancer progression by deSUMOylation of SETDB1 and regulating GLI2 transcription Zhe Wang1 · Ze Yang2 · Yong Chen3 · Xiaojing Zhao1 · Dengfeng Gao4 · Nancy Wang5 · Albert Williams6 Received: 19 November 2025 / Accepted: 2 April 2026 © The Author(s) 2026 Abstract SUMO-specific protease 3 (SENP3) was reported to be dysregulated in osteosarcoma and ovarian cancer. However, the role of SENP3 in carcinogenesis of papillary thyroid cancer (PTC) has not been defined. Herein, we found that the expression of SENP3 protein was upregulated in PTC tissues and cell lines. Then, a PTC cell line, K-1 cells were transfected with SENP3 overexpression plasmid (pcDNA-SENP3) or small interfering RNA targeting SENP3 (SENP3 siRNA) . We found that SENP3 overexpression facilitated cell proliferation and invasion, induced cell cycle arrest at G0/G1 phase and inhibited apoptosis in PTC cells, whereas SENP3 knockdown showed the opposite results. We further found that SET domain bifurcated 1 (SETDB1) can be regulated by SENP3-dependent deSUMOylation. Furthermore, SUMOylation of SETDB1 promoted SETDB1 to form a complex with MBD1-containing chromatin-associated factor 1 (MCAF1), and in turn to occupy the promoter locus of GLI family zinc finger 2 (GLI2) gene to suppress GLI2 expression through trimethylation of histone H3 Lys9 (H3K9me3) . Then rescue experiments showed that GLI2 overexpression reversed the effects of SENP3 silencing on K-1 cell functions. The PI3K/AKT pathway inhibitor XL147 suppressed the effects of SENP3 overexpression on K-1 cell behaviors. Additionally, SENP3 knockdown significantly inhibited the xenograft tumor growth of PTC in vivo. This study revealed that SENP3 promoted PTC progression in vitro and in vivo by deSUMOylating SETDB1, thereby relieving SETDB1-mediated repression of GLI2 H3K9 trimethylation, which may provide a potential therapeutic target for PTC. Keywords Papillary thyroid cancer · SENP3 · SETDB1 · GLI2 · PI3K/AKT pathway 􀀍 Albert Williams [albertwilliams@yeah.net](albertwilliams@yeah.net) 1 Department of General Medical, The Second Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710004, China 2 Department of Clinical Laboratory, The Affiliated Central Hospital of Shenyang Medical College, Shenyang 110000, China 3 Department of Endoscopy Center, Shaanxi Cancer Hospital, Xi’an 710061, China 4 Department of Cardiology, The Second Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710004, China 5 Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen 2200, Denmark 6 LKS Faculty of Medicine, The University of Hongkong, Pokfulam Hong Kong 999077, China Abbreviations SENP3 SUMO-specific protease 3 PTC papillary thyroid cancer siRNA small interfering RNA ChIP immunoprecipitation assay CCK-8 cell counting kit-8 OD optical density SEM standard error of mean GAPDH glyceraldehyde 3-phosphate dehydrogenase IHC immunohistochemical ANOVA analysis of variance 1 3 Introduction Thyroid cancer (TC) is the most prevalent cancer in the endocrine system, whose incidence and morbidity are steadily growing around the world [1] . Papillary thyroid cancer (PTC) is the most common histopathological subtype of TC, accounting for approximately 90% of all TC cases. Risk factors for PTC include gene mutations and environmental exposures. Most patients with early PTC have a good prognosis after thyroidectomy and radioiodine therapy. However, if metastasis is present, the recurrence rate is greatly increased [2] . Therefore, it remains important to understand the molecular mechanisms of PTC progression. In addition, there remains a need to identify novel molecular targets and therapeutic strategies for PTC. SU

FAQs

What effect does SENP3 have on papillary thyroid cancer cells?

SENP3 overexpression promotes K-1 cell proliferation and invasion, induces G0/G1 cell cycle arrest, and inhibits apoptosis, while SENP3 knockdown produces opposite results.

How does SENP3 regulate GLI2 expression in the proposed mechanism?

SENP3-dependent deSUMOylation regulates SETDB1, enabling SETDB1 to form a complex with MCAF1 and occupy the GLI2 promoter to suppress GLI2 expression through H3K9 trimethylation.

Which experimental strategies confirm the pathway and therapeutic relevance?

Rescue experiments show that GLI2 overexpression reverses SENP3-silencing effects on K-1 cell functions, and the PI3K/AKT inhibitor XL147 suppresses SENP3 overexpression-driven behaviors; additionally, SENP3 knockdown reduces xenograft tumor growth in vivo.

Sep 23, 2026

Uploaded by Franzy