ALKBH5 inhibits the SIRT3/ACC1 axis to regulate fatty acid metabolism via an m6A‐IGF2BP1‐dependent manner in cervical squamous cell carcinoma

• Published in: Clinical and experimental pharmacology & physiology Vol. 50; no. 5; pp. 380 - 392
• Main Authors: Zhen, Lan, Pan, Wuyuan
• Format: Journal Article
• Language: English
• Published: Australia Wiley Subscription Services, Inc 01.05.2023
• Subjects: AlkB Homolog 5, RNA Demethylase - genetics; AlkB Homolog 5, RNA Demethylase - metabolism; ALKBH5cervical squamous cell carcinomafatty acid metabolismN6‐methyladenosine; Bioinformatics; Cancer; Carcinoma, Squamous Cell - genetics; Cervical cancer; Cervix; Deacetylation; Fatty Acids; Female; Growth factors; Humans; Immunoprecipitation; Insulin; Lipid Metabolism; Lipids; Low level; Malignancy; Medical prognosis; Metabolism; Methylation; N6-methyladenosine; Polymerase chain reaction; Reproductive system; Reverse transcription; RNA - metabolism; Sirtuin 3 - genetics; Sirtuin 3 - metabolism; Squamous cell carcinoma; Tissues; Tumorigenesis; Tumors; Uterine Cervical Neoplasms - genetics; Western blotting; Wound healing; ALKBH5cervical squamous cell carcinomafatty acid metabolismN6-methyladenosine
• ISSN: 0305-1870; 1440-1681
• DOI: 10.1111/1440-1681.13754

Cervical cancer (CC) is the most common malignancy of the female reproductive system, among which cervical squamous cell carcinoma (CESC) is the most common type. The demethylase ALKBH5 has been previously revealed to be downregulated in CC tissue. N6 methyladenine (m6A) is the most common modification in eukaryotic RNAs and is involved in modulating tumour progression. Therefore, we attempted to clarify the ALKBH5 role and mechanism underlying CESC progression. In CESC, patient tissue and control tissue m6A levels were measured. Reverse transcription quantitative real‐time polymerase chain reaction, western blotting and immunochemistry were used to measure ALKBH5 levels. A correlation between CESC patient survival and ALKBH5 levels was evaluated. Wound healing, transwell and colony formation assays were used to detect CESC cellular behaviours. Corresponding kits and BODIPY staining were used to detect CESC lipid metabolism. Bioinformatics, immunoprecipitation, RNA pulldown and RNA immunoprecipitation assays as well as half‐life measurements were used to assess the association and mechanism of ALKBH5 with silent mating type information regulation 2 homologue 3 (SIRT3), acetyl‐CoA carboxylase 1 (ACC1) and insulin‐like growth factor 2 mRNA binding protein 1 (IGF2BP1). The m6A demethylase ALKBH5 was depleted in CESC tissue and cells, and a low level of ALKBH5 predicted an unfavourable prognosis in CESC patients. ALKBH5 overexpression suppressed CESC growth and lipid metabolism in vitro and CESC tumour growth in vivo, and ACC1 overexpression rescued these changes. ALKBH5 downregulated ACC1 levels in CESC cells by facilitating SIRT3 methylation to repress ACC1 deacetylation. ALKBH5 destabilized SIRT3 to downregulate SIRT3 levels in CESCs in an m6A‐IGF2BP1‐dependent manner. ALKBH5 demethylates and destabilizes SIRT3 in an m6A‐IGF2BP1‐dependent manner, repressing CESC growth, lipid metabolism and tumorigenesis by downregulating ACC1. The expression level of the N6 methyladenine (m6A) demethylase ALKBH5 is decreased in cervical squamous cell carcinoma (CESC); consequently, the RNA methylation level of silent mating type information regulation 2 homologue 3 (SIRT3) is abnormally upregulated and recognized by the m6A reading protein insulin‐like growth factor 2 mRNA binding protein 1 (IGF2BP1), which promotes the mRNA stabilization of SIRT3 and increases SIRT3 expression levels. SIRT3, then, mediates the deacetylation of the fatty acid synthase acetyl‐CoA carboxylase 1 (ACC1) to increase ACC1 protein expression, which regulates fatty acid metabolism to promote CESC progression.