2. Academic Validation
  3. Dual specific phosphatase 4 suppresses ferroptosis and enhances sorafenib resistance in hepatocellular carcinoma

Dual specific phosphatase 4 suppresses ferroptosis and enhances sorafenib resistance in hepatocellular carcinoma

  • Drug Resist Updat. 2024 Mar:73:101052. doi: 10.1016/j.drup.2024.101052.
Shi-Hui Hao 1,  Xiao-Dan Ma 2,  Li Xu 3,  Jing-Dun Xie 4,  Zi-Hao Feng 5,  Jie-Wei Chen 6,  Ri-Xin Chen 7,  Feng-Wei Wang 2,  Yu-Hao Tang 3,  Dan Xie 8,  Mu-Yan Cai 9
Affiliations

Affiliations

  • 1 Department of Nuclear Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 2 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 510060 Guangzhou, China.
  • 3 Department of Liver Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 4 Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China.
  • 5 Department of Urology, the First Affiliated Hospital, Sun Yat-sen University, 510060 Guangzhou, China.
  • 6 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 510060 Guangzhou, China; Department of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 7 Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; Department of Thoracic Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
  • 8 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 510060 Guangzhou, China; Department of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: [email protected].
  • 9 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 510060 Guangzhou, China; Department of Pathology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. Electronic address: [email protected].
PMID: 38262246 DOI: 10.1016/j.drup.2024.101052
Abstract

Aims: This investigation aims to elucidate the mechanism underlying sorafenib-induced Ferroptosis in hepatocellular carcinoma (HCC).

Methods: The role of dual specificity Phosphatase 4 (DUSP4) in sorafenib-treated HCC was investigated using comprehensive assessments both in vitro and in vivo, including Western blotting, qRT-PCR, cell viability assay, lipid Reactive Oxygen Species (ROS) assay, immunohistochemistry, and xenograft tumor mouse model. Additionally, label-free quantitative proteomics was employed to identify potential proteins associated with DUSP4.

Results: Our study revealed that suppression of DUSP4 expression heightens the susceptibility of HCC cells to Ferroptosis inducers, specifically sorafenib and erastin, in both in vitro and in vivo settings. Furthermore, we identified DUSP4-mediated regulation of key ferroptosis-related markers, such as ferritin light chain (FTL) and ferritin heavy chain 1 (FTH1). Notably, label-free quantitative proteomics unveiled the phosphorylation of threonine residue T148 on YTH Domain Containing 1 (YTHDC1) by DUSP4. Further investigations unraveled that YTHDC1, functioning as an mRNA nuclear export regulator, is a direct target of DUSP4, orchestrating the subcellular localization of FTL and FTH1 mRNAs. Significantly, our study highlights a strong correlation between elevated DUSP4 expression and sorafenib resistance in HCC.

Conclusions: Our findings introduce DUSP4 as a negative regulator of sorafenib-induced Ferroptosis. This discovery opens new avenues for the development of ferroptosis-based therapeutic strategies tailored for HCC treatment.

Keywords

DUSP4; Ferroptosis; Hepatocellular carcinoma; Sorafenib resistance; YTHDC1.

Figures
Products