ATF1 promotes ferroptosis resistance in lung cancer through enhancing mRNA stability of PROM2.

Hu, Minjie; Yang, Jiali; Tan, Zusong

Hu, Minjie; Yang, Jiali; Tan, Zusong.

Afiliación

Hu M; Department of Thoracic Cardiovascular Surgery, The First Affiliated Hospital of Nanhua University, Hengyang, 421000, Hunan Province, China.
Yang J; Disinfection Supply Center, The First Affiliated Hospital of Nanhua University, Hengyang, 421000, Hunan Province, China.
Tan Z; Department of Thoracic Cardiovascular Surgery, The First Affiliated Hospital of Nanhua University, Hengyang, 421000, Hunan Province, China. Electronic address: 2018011451@usc.edu.cn.

Exp Cell Res ; 442(1): 114190, 2024 Sep 01.

Article en En | MEDLINE | ID: mdl-39098467

ABSTRACT

ABSTRACT

BACKGROUND:

Ferroptotic proteins are promising therapeutic targets for lung cancer. The PROM2 is upregulated in lung cancer and known to suppress ferroptosis. This study examined the molecular mechanisms for PROM2-induced ferroptosis resistance in lung cancer.

METHODS:

Ferroptosis in lung cancer was assessed by iron kit, and transmission electron microscopy was applied to observe the changes in mitochondrial morphology. BODIPY™ was applied to test the lipid ROS, and MeRIP was performed to test the m6A modification of PROM2. RIP assay was employed for confirming the binding between METTL3 and PROM2. In addition, dual luciferase assay was employed for exploring the transcriptional regulation of ATF1 to METTL3, and the binding relation between ATF1 and METTL3 promoter region was explored by ChIP assay.

RESULTS:

Expression levels of PROM2 were significantly higher in lung cancer cell lines than a noncancerous control line, and PROM2 knockdown significantly reduced both cancer cell viability and proliferation rate. In addition, PROM2 knockdown reduced xenograft tumor growth and exacerbated erastin-induced ferroptosis. Compared to PROM2 mRNA from control cells, transcripts in lung cancer cells exhibited enhanced m6A levels, and showed greater binding with METTL3. Further, ATF1 upregulated METTL3 transcription, thereby stabilizing PROM2 mRNA and increasing ferroptosis resistance.

CONCLUSION:

ATF1 could promote ferroptosis resistance in lung cancer through enhancing mRNA stability of PROM2. Thus, our work might shed novel insights on discovering therapeutic strategy for lung cancer.

Asunto(s)

Ferroptosis; Regulación Neoplásica de la Expresión Génica; Neoplasias Pulmonares; Estabilidad del ARN; Ferroptosis/genética; Humanos; Neoplasias Pulmonares/genética; Neoplasias Pulmonares/patología; Neoplasias Pulmonares/metabolismo; Estabilidad del ARN/genética; Animales; Ratones; Ratones Desnudos; Línea Celular Tumoral; Proliferación Celular/genética; Metiltransferasas/genética; Metiltransferasas/metabolismo; ARN Mensajero/genética; ARN Mensajero/metabolismo; Ensayos Antitumor por Modelo de Xenoinjerto; Ratones Endogámicos BALB C; Células A549

Palabras clave

ATF1; METTL3; PROM2; m6A modification

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación Neoplásica de la Expresión Génica / Estabilidad del ARN / Ferroptosis / Neoplasias Pulmonares Límite: Animals / Humans Idioma: En Revista: Exp Cell Res Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos

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