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

Zhang, Qiangnu1,2,3; Xiong, Lingfeng1,2; Wei, Teng2,4; Liu, Quan5; Yan, Lesen1,2; Chen, Jiaojuan1,2; Dai, Lu6; Shi, Lulin1,2; Zhang, Wenjian1,2; Yang, Jilin1,2; Roessler, Stephanie7; Liu, Liping1,2

2023-03-01

10.1038/s41388-023-02665-y

ONCOGENE   Impact Factor & Quartile

0950-9232

1476-5594

Emerging evidence has indicated that peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (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/beta-catenin signaling. BAMBI mediated the function of PPARGC1A and regulated ACSL5 through TGF-beta/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.

SCI

English

Corresponding

China Postdoctoral Science Foundation[2021M701426] ; Shenzhen Science and Technology Innovation Commission Foundation[JCYJ20190806160412946] ; Guangdong Basic and Applied Basic Research Foundation["2021A1515220059","2019A1515110149"] ; National Natural Science Foundation of China["82002956","8140204"]

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

WOS:000951990200001

SPRINGERNATURE

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2, Dept Gen Surg,Div Hepatobiliary & Pancreas Surg, Shenzhen 518020, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Peoples R China
3.Jinan Univ, Integrated Chinese & Western Med Postdoctoral Res, Guangzhou 510632, Peoples R China
4.Jinan Univ, Shenzhen Peoples Hosp, The Clin Med Coll 2, Cytotherapy Lab, Shenzhen 518020, Peoples R China
5.Huazhong Univ Sci & Technol, Union Shenzhen Hosp, Nanshan Hosp, Lab Med Ctr, Shenzhen 518000, Peoples R China
6.Southern Univ Sci & Technol, Sch Med, Shenzhen 518055, Guangdong, Peoples R China
7.Heidelberg Univ Hosp, Inst Pathol, D-69120 Heidelberg, Germany

Zhang, Qiangnu,Xiong, Lingfeng,Wei, Teng,et al. Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma[J]. ONCOGENE,2023.

Zhang, Qiangnu.,Xiong, Lingfeng.,Wei, Teng.,Liu, Quan.,Yan, Lesen.,...&Liu, Liping.(2023).Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma.ONCOGENE.

Zhang, Qiangnu,et al."Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma".ONCOGENE (2023).