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

Oncogene volume 42, pages 1509–1523 (2023)Cite this article

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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.

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Fig. 1: PPARGC1A was significantly downregulated in HCC and low PPARGC1A indicated a poor prognosis.
Fig. 2: PPARGC1A negatively regulated BAMBI in HCC via Wnt/β-catenin signaling.
Fig. 3: The PPARGC1A/BAMBI axis was involved with progression of HCC and sensitivity to lenvatinib.
Fig. 4: ACSL5 was regulated by PPARGC1A/BAMBI axis in a TGF-β/Smad signaling-dependent way.
Fig. 5: PPARGC1A/BAMBI influenced ROS production and sensitivity to ferroptosis by regulating ACSL5.
Fig. 6: PPARGC1A was hypoxia-responsive and epigenetically regulated by m6A modification induced by METTL3 or WTAP in a YTHDF2-dependent way.
Fig. 7: Metformin enhanced PPARGC1A levels by reducing m6A mRNA methylation.
Fig. 8: Aberrant PPARGC1A/BAMBI/ACSL5 axis changes and their function were validated in animal or patient models.

Data availability

All data included in this study are available upon request by contact with the corresponding author.

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Funding

This study was supported by the China Postdoctoral Science Foundation (2021M701426), Shenzhen Science and Technology Innovation Commission Foundation (JCYJ20190806160412946) and Guangdong Basic and Applied Basic Research Foundation (2021A1515220059, 2019A1515110149) and the National Natural Science Foundation of China (82002956, 8140204).

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Author notes

  1. These authors contributed equally: Qiangnu Zhang, Linfeng Xiong.

Authors and Affiliations

  1. Division of Hepatobiliary and Pancreas Surgery, Department of General Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), 518020, Shenzhen, China

    Qiangnu Zhang, Lingfeng Xiong, Lesen Yan, Jiaojuan Chen, Lulin Shi, Wenjian Zhang, Jilin Yang & Liping Liu

  2. Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, 510632, Guangzhou, China

    Qiangnu Zhang

  3. Cytotherapy Laboratory, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), 518020, Shenzhen, China

    Teng Wei

  4. Laboratory Medicine Center, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), 518000, Shenzhen, China

    Quan Liu

  5. School of Medcine, Southern University of Science and Technology, 518055, Shenzhen, Guangdong, China

    Lu Dai

  6. Institute of Pathology, Heidelberg University Hospital, 69120, Heidelberg, Germany

    Stephanie Roessler

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Contributions

QNZ, LPL designed the study. LPL supervised the study. QNZ, LFX and TW carried out the experimental work. SR collected, provided and interpreted HCC datasets used in the present study. QNZ, QL and DL performed data processing and bioinformatics analyses. QNZ wrote the manuscript. LSY, LLS and JJC helped with the animal experiments. The article was reviewed and approved for publication by all authors.

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Correspondence to Liping Liu.

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Zhang, Q., Xiong, L., Wei, T. et al. Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma. Oncogene 42, 1509–1523 (2023). https://doi.org/10.1038/s41388-023-02665-y

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