Monthly Archives: 3 月 2026

趙瑞益教授研究團隊發表研究成果於J Adv Res.

連結網址：https://pubmed.ncbi.nlm.nih.gov/41730411/

Abstract

Introduction: Biomolecular condensates are membraneless organelles functionally involved in diverse processes, including cancer progression. Sequestosome-1 (SQSTM1)/p62 regulates liquid-liquid phase separation to drive biomolecular condensates, while programmed death-ligand 1 (PD-L1) promotes cancer cell growth. Although SQSTM1 has been shown to form condensates with several complexes, its full range of partners remains incompletely characterized.

Objectives: This study aimed to investigate the role of SQSTM1 in mediating PD-L1 condensate formation and its contribution to lung tumorigenesis.

Methods: The SQSTM1-PD-L1 interaction and condensate colocalization were examined by immunoprecipitation and immunofluorescence. Truncated SQSTM1 constructs validate the interacting domain with PD-L1, which is supported by computational AlphaFold3 analysis. We applied 1,6-hexanediol, FDA-approved PD-L1 antibody Atezolizumab, and CRISPR/Cas9-based SQSTM1 knockout to disrupt SQSTM1/PD-L1 biomolecular condensates, along with in vitro and in vivo experiments. The Survivin levels were analyzed using real-time quantitative PCR and immunoblotting. Clinical correlations of SQSTM1 and PD-L1 expression with prognosis were assessed using public datasets.

Results: Our research demonstrate that SQSTM1, by its Phox1 and Bem1 (PB1) domain, directly interacts with PD-L1 to facilitate the SQSTM1/PD-L1 biomolecular condensate formation. The formation of SQSTM1/PD-L1 condensates prevents PD-L1 from ubiquitin-proteasome-mediated degradation and stabilizes PD-L1 levels. Deletion of the PB1 domain in SQSTM1 inhibits the formation of PD-L1 biomolecular condensates and induces PD-L1 K48 ubiquitination for protein degradation. Disruption of SQSTM1/PD-L1 condensates with 1,6-hexanediol induces PD-L1 proteolysis and reduces cell viability. Knockout of SQSTM1 disrupts PD-L1 condensate formation, downregulates PD-L1 protein levels, and attenuates tumor growth. Treatment with PD-L1 antibody drug Atezolizumab inhibits SQSTM1/PD-L1 condensates and suppresses tumor formation. Clinically, high SQSTM1 and PD-L1 expression correlated with poor prognosis in lung cancer patients.

Conclusion: Together, the SQSTM1 directly interacts with non-membrane-associated PD-L1 to drive the formation of SQSTM1/PD-L1 biomolecular condensates, which prevent PD-L1 degradation, promote lung tumorigenesis, and serve as a potential therapeutic target in lung cancers.

Keywords: Biomolecular condensate; PB1 domain; PD-L1; SQSTM1; Tumorigenesis.

陳亭妏副教授研究團隊發表研究成果於J Hepatol.

連結網址：https://pubmed.ncbi.nlm.nih.gov/39763896/

Abstract

Most malignant hepatocellular tumors in children are classified as either hepatoblastoma (HB) or hepatocellular carcinoma (HCC), but some tumors demonstrate features of both HB and HCC^1-3. These tumors have been recognized under a provisional diagnostic category by the World Health Organization and are distinguished from HB and HCC by a combination of histological, immunohistochemical, and molecular features^4-6. Their outcomes and cellular composition remain an open question^7-9. The heterogeneous histological and molecular profiles of hepatoblastomas with carcinoma features (HBCs)⁴ may result from cells with combined HB and HCC characteristics (HBC cells) or from mixtures of cells displaying either HB or HCC signatures. We used multiomics profiling to show that HBCs are mixtures of HB, HBC, and HCC cell types. HBC cells are more chemoresistant than HB cells, and their chemoresistance-a driver of poor outcomes^10-12-is determined by their cell types, genetic alterations, and embryonic differentiation stages. We showed that the prognosis of HBCs is significantly worse than that of HBs. We also showed that HBC cells are derived from HB cells at early hepatoblast differentiation stages, that aberrant activation of WNT-signaling initiates HBC transformation, and that WNT inhibition promotes differentiation and increases sensitivity to chemotherapy. Furthermore, our analysis revealed that each HBC is the product of multiple HB-to-HBC and HBC-to-HCC transitions. Thus, multiomics profiling of HBCs provided key insights into their biology and resolved major questions regarding the etiology of these childhood liver tumors.

張晉源副教授研究團隊發表研究成果於J Am Chem Soc.

連結網址：https://pubmed.ncbi.nlm.nih.gov/41779877/

Abstract

The biosynthesis of α-cyclopiazonic acid (α-CPA) is notable for generating a complex pentacyclic scaffold using a minimal three-enzyme pathway. The final step, catalyzed by CpaO, converts linear β-CPA into α-CPA through an enigmatic oxidative cyclization. Here, we report the structural and mechanistic characterization of CpaO. X-ray crystallography reveals a three-domain architecture belonging to the flavin-dependent amine oxidase (FAO) superfamily, while CpaO represents a previously undescribed subfamily distinguished by an essential, covalently linked FAD (8α-N¹-histidyl) and divergent substrate-binding domains. High-resolution structures of the CpaO/β-CPA complex, validated by mutagenesis, identify key active-site residues (His165, Trp317, Asp412, Tyr283) that anchor the substrate. Combined structural, mutational, and molecular dynamics analyses further suggest distinct yet cooperative roles for Tyr283 and Ser167 in modulating substrate access and subsequent binding. Derived from these data, we propose a stereospecific mechanism initiated by FAD-mediated hydride abstraction, which triggers a bicyclization cascade to form the final C and D rings. This study resolves a long-standing biosynthetic mystery and expands the catalytic repertoire of flavoenzymes, offering a template for the chemoenzymatic synthesis of complex indole alkaloids.