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

Abstract

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.

Critical roles and clinical perspectives of RNA methylation in cancer

“…In AML, IGF2BP2 stabilizes protein arginine methyltransferase 6 (PRMT6) and subsequently downregulates the expression of the lipid transporter major facilitator superfamily domain containing 2A (MFSD2A), thereby maintaining the function of leukemia stem cells 414 . In CC, depleted levels of the demethylase ALKBH5 indicate an unfavorable prognosis, and ALKBH5 functionally suppresses the expression of silent mating type information regulation 2 homologue 3 and ACC1 in an IGF2BP1‐dependent manner, ultimately inhibiting FA synthesis 415 . In bladder cancer, METTL14 induces lncDBET overexpression, and along with FA binding protein 5 (FABP5), it promotes lipid metabolism and the malignant progression of bladder cancer 416 .…”

“… 414 In CC, depleted levels of the demethylase ALKBH5 indicate an unfavorable prognosis, and ALKBH5 functionally suppresses the expression of silent mating type information regulation 2 homologue 3 and ACC1 in an IGF2BP1‐dependent manner, ultimately inhibiting FA synthesis. 415 In bladder cancer, METTL14 induces lncDBET overexpression, and along with FA binding protein 5 (FABP5), it promotes lipid metabolism and the malignant progression of bladder cancer. 416 In GBM, constitutively activated EGFR/SRC/ERK pathway results in YTHDF2 overexpression and subsequently downregulate LXRA and HIVEP2 expression, thereby disrupting cholesterol homeostasis and sustaining GBM tumorigenesis.…”

RNA modifications in cellular metabolism: implications for metabolism-targeted therapy and immunotherapy

“…ALKBH5 attenuated stability of SIRT3 mRNA in an IGF2BP1-dependent manner, further reduced ACC1 level repress its deacetylation, thus suppresses fatty acid synthesis to modulate CESC lipid metabolism. 327 …”

Lipid metabolic reprogramming by traditional Chinese medicine and its role in effective cancer therapy

“…Liu et al [40] showed that ACC depletion suppresses de novo fatty acid synthesis and mitochondrial beta-oxidation in the synthesis of acetyl-Coa carboxylase castration-resistant prostate cancer cells. Moreover, many studies have found that regulating fatty acid levels by interfering with ACC expression can help inhibit tumor growth [41][42][43]. Therefore, ACC1 inhibition has become an appealing choice for antitumor therapy [43,44].…”