2. Academic Validation
  3. N6-methyladenosine modification of LATS2 promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis

N6-methyladenosine modification of LATS2 promotes hepatoblastoma progression by inhibiting ferroptosis through the YAP1/ATF4/PSAT1 axis

  • Int J Biol Sci. 2024 Aug 1;20(11):4146-4161. doi: 10.7150/ijbs.92413.
Guoqing Zhu 1,  Yi Xie 1,  Zhixuan Bian 1,  Ji Ma 1,  Ni Zhen 1,  Tianshu Chen 1,  Jiabei Zhu 1,  Siwei Mao 1,  Xiaochen Tang 1,  Li Liu 1,  Song Gu 2,  Miao Ding 1,  Qiuhui Pan 1 3 4 5
Affiliations

Affiliations

  • 1 Clinical Laboratory, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P. R. China.
  • 2 Department of Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P. R. China.
  • 3 Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai 200127, P. R. China. Address: Dongfang Road No. 1678, Pudong New District, Shanghai 200127, P. R. China.
  • 5 Sanya Women and Children's Hospital Managed by Shanghai Children's Medical Center, Sanya 572000, P. R. China.
PMID: 39247829 DOI: 10.7150/ijbs.92413
Abstract

Ferroptosis has attracted extensive interest from Cancer researchers due to its substantial potential as a therapeutic target. The role of LATS2, a core component of the Hippo pathway cascade, in Ferroptosis initiation in hepatoblastoma (HB) has not yet been investigated. Furthermore, the underlying mechanism of decreased LATS2 expression remains largely unknown. In the present study, we demonstrated decreased LATS2 expression in HB and that LATS2 overexpression inhibits HB cell proliferation by inducing Ferroptosis. Increased LATS2 expression reduced glycine and cysteine concentrations via the ATF4/PSAT1 axis. Physical binding between YAP1/ATF4 and the PSAT1 promoter was confirmed through ChIP‒qPCR. Moreover, METTL3 was identified as the writer of the LATS2 mRNA m6A modification at a specific site in the 5' UTR. Subsequently, YTHDF2 recognizes the m6A modification site and recruits the CCR4-NOT complex, leading to its degradation by mRNA deadenylation. In summary, N6-methyladenosine modification of LATS2 facilitates its degradation. Reduced LATS2 expression promotes hepatoblastoma progression by inhibiting Ferroptosis through the YAP1/ATF4/PSAT1 axis. Targeting LATS2 is a potential strategy for HB therapy.

Keywords

Hippo/YAP; LATS2; ferroptosis; hepatoblastoma; m6A methylation.

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