Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma.

Abstract

Emerging evidence has indicated that peroxisome proliferator-activated receptor-gamma coactivator-1α (PPARGC1A) is involved in hepatocellular carcinoma (HCC). However, its detailed function and up- and downstream mechanisms are incompletely understood. In this study, we confirmed that PPAGC1A is lowly expressed in HCC and is associated with poor prognosis using large-scale public datasets and in-house cohorts. PPAGC1A was found to impair the progression and sensitivity of HCC to lenvatinib. Mechanistically, PPAGC1A repressed bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) by inhibiting WNT/β-catenin signaling. BAMBI mediated the function of PPARGC1A and regulated ACSL5 through TGF-β/SMAD signaling. PPARGC1A/BAMBI regulated ROS production and ferroptosis-related cell death by controlling ACSL5. PPARGC1A/BAMBI/ACSL5 axis was hypoxia-responsive. METTL3 and WTAP silenced PPARGC1A in an m6A-YTHDF2-dependent way under normoxia and hypoxia, respectively. Metformin restored PPARGC1A expression by reducing its m6A modification via inhibiting METTL3. In animal models and patient-derived organoids, consistent functional data of PPARGC1A/BAMBI/ACSL5 were observed. Conclusions: These findings provide new insights into the role of the aberrant PPARGC1A/BAMBI/ACSL5 axis in HCC. And the mechanism of PPARGC1A dysregulation was explained by m6A modification. Metformin may benefit HCC patients with PPARGC1A dysregulation.

• Authors: Qiangnu Zhang, Lingfeng Xiong, Teng Wei, Quan Liu, Lesen Yan, Jiaojuan Chen, Lu Dai, Lulin Shi, Wenjian Zhang, Jilin Yang, Stephanie Roessler, Liping Liu
• Journal: Oncogene (Oncogene) Vol. 42 Issue 19 Pg. 1509-1523 (05 2023) ISSN: 1476-5594 [Electronic] England
• PMID: 36932115 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• lenvatinib
• Metformin
• PPAR gamma
• BAMBI protein, human
• ACSL5 protein, human
• PPARGC1A protein, human

Topics

• Animals
• Humans
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism)
• Liver Neoplasms (drug therapy, genetics, metabolism)
• Metformin
• PPAR gamma