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SP1 undergoes phase separation and activates RGS20 expression through super-enhancers to promote lung adenocarcinoma progression.
Shan, Liying; Wang, Wenmeng; Du, Lijuan; Li, Dangdang; Wang, Yunxuan; Xie, Yuyan; Li, Hongyan; Wang, Jiale; Shi, Zhihao; Zhou, Yang; Zhu, Daling; Sui, Guangchao; Liu, Fang.
Afiliación
  • Shan L; Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
  • Wang W; College of Life Science, Northeast Forestry University, Harbin 150040, China.
  • Du L; Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
  • Li D; College of Life Science, Northeast Forestry University, Harbin 150040, China.
  • Wang Y; Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
  • Xie Y; Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
  • Li H; Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
  • Wang J; Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
  • Shi Z; Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
  • Zhou Y; Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
  • Zhu D; College of Pharmacy, Harbin Medical University (Daqing), Daqing 163319, China.
  • Sui G; College of Life Science, Northeast Forestry University, Harbin 150040, China.
  • Liu F; Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
Proc Natl Acad Sci U S A ; 121(29): e2401834121, 2024 Jul 16.
Article en En | MEDLINE | ID: mdl-38976739
ABSTRACT
Lung adenocarcinoma (LUAD) is the leading cause of cancer-related death worldwide, but the underlying molecular mechanisms remain largely unclear. The transcription factor (TF) specificity protein 1 (SP1) plays a crucial role in the development of various cancers, including LUAD. Recent studies have indicated that master TFs may form phase-separated macromolecular condensates to promote super-enhancer (SE) assembly and oncogene expression. In this study, we demonstrated that SP1 undergoes phase separation and that its zinc finger 3 in the DNA-binding domain is essential for this process. Through Cleavage Under Targets & Release Using Nuclease (CUT&RUN) using antibodies against SP1 and H3K27ac, we found a significant correlation between SP1 enrichment and SE elements, identified the regulator of the G protein signaling 20 (RGS20) gene as the most likely target regulated by SP1 through SE mechanisms, and verified this finding using different approaches. The oncogenic activity of SP1 relies on its phase separation ability and RGS20 gene activation, which can be abolished by glycogen synthase kinase J4 (GSK-J4), a demethylase inhibitor. Together, our findings provide evidence that SP1 regulates its target oncogene expression through phase separation and SE mechanisms, thereby promoting LUAD cell progression. This study also revealed an innovative target for LUAD therapies through intervening in SP1-mediated SE formation.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación Neoplásica de la Expresión Génica / Factor de Transcripción Sp1 / Proteínas RGS / Adenocarcinoma del Pulmón / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación Neoplásica de la Expresión Génica / Factor de Transcripción Sp1 / Proteínas RGS / Adenocarcinoma del Pulmón / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos