The prognostic role of ACSL4 in postoperative adjuvant TACE-treated HCC: implications for therapeutic response and
Ji Feng1,2,3, Jin-Lian Bin2, Xi-Wen Liao4
1School of Public Health, Fudan University, 130 Dong-An Road, Shanghai, 200032, China.
Background:
The response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE) treatment and its underlying mechanisms remain elusive. This study investigates the role of enzymes involved in fatty acid activation, specifically Acyl-CoA synthetase long chain 4 (ACSL4), in HCC patients treated with postoperative adjuvant TACE (PA-TACE) and in nutrient-deprived HCC cells.
Methods:
We examined the expression of ACSL4 and its family members in HCC clinical samples and cell lines. The clinical significance of ACSL4, particularly regarding the prognosis of patients treated with PA-TACE, was assessed using two independent HCC cohorts. We further explored the role of ACSL4 in glucose starvation-induced cell death in HCC cells and xenograft mouse models.
Results:
Among the family members, ACSL4 is the most up-regulated enzyme, associated with poor survival in HCC patients, particularly in post-recurrent TACE-treated patients in a Singapore cohort. ACSL4 is essential for HCC cell survival in response to glucose starvation, rather than to hypoxia or to the combination of hypoxia with doxorubicin or cisplatin. ACSL4-mediated arachidonic acid (AA) metabolism supports mitochondrial β-oxidation and energy production. CCAAT/enhancer binding protein α (CEBPA) transcriptionally regulates ACSL4 by binding 3 motifs (-623 to -613, -1197 to -1187 and -1745 to -1735) of ACSL4 upstream promoter region, enhancing its pro-survival effects. Furthermore, canagliflozin (Cana), a clinical-approved drug for type 2 diabetes, mimics glucose starvation and inhibits the growth of ACSL4-low xenograft tumors. Moreover, high ACSL4 or CEBPA expressions correlate with increased recurrence susceptibility after PA-TACE in the China-Guangxi HCC cohort.
Conclusions:
The CEBPA-ACSL4 pathway is critical in protecting HCC cells from glucose starvation-induced cell death, suggesting that ACSL4 and CEBPA could serve as valuable prognostic indicators and potential therapeutic targets in the context of PA-TACE treatment for HCC.
Insights
Acyl-CoA synthetase long chain 4 (ACSL4) is crucial for hepatocellular carcinoma (HCC) cell survival during glucose starvation. Targeting the CEBPA-ACSL4 pathway may improve outcomes for HCC patients receiving transarterial chemoembolization (TACE) treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) treatment response to transarterial chemoembolization (TACE) and its mechanisms are not fully understood.
- This study focuses on Acyl-CoA synthetase long chain 4 (ACSL4), an enzyme in fatty acid activation, within the context of HCC.
- Investigates ACSL4's role in HCC patients undergoing postoperative adjuvant TACE (PA-TACE) and in nutrient-deprived HCC cells.
Purpose of the Study:
- To investigate the role of ACSL4 in HCC.
- To determine the clinical significance of ACSL4 expression in HCC patients treated with PA-TACE.
- To explore ACSL4's function in HCC cell survival under glucose starvation.
Main Methods:
- Examined ACSL4 and related enzyme expression in HCC clinical samples and cell lines.
- Assessed the prognostic value of ACSL4 in two independent HCC cohorts, focusing on PA-TACE treated patients.
- Investigated ACSL4's role in glucose starvation-induced cell death using HCC cell and xenograft mouse models.
Main Results:
- ACSL4 is the most upregulated enzyme, linked to poor survival in HCC patients, especially those treated with PA-TACE.
- ACSL4 is vital for HCC cell survival under glucose starvation, supporting energy production via arachidonic acid metabolism.
- The CEBPA-ACSL4 pathway enhances cell survival; canagliflozin inhibits growth in ACSL4-low tumors. High ACSL4/CEBPA correlates with recurrence after PA-TACE.
Conclusions:
- The CEBPA-ACSL4 pathway is critical for protecting HCC cells against glucose starvation.
- ACSL4 and CEBPA show potential as prognostic indicators for HCC patients.
- Targeting ACSL4 and CEBPA presents a potential therapeutic strategy for HCC patients undergoing PA-TACE.
