2. Academic Validation
  3. Valproic acid promotes transcriptional activation of Drd2 by mediating histone acetylation to inhibit the mTOR-Pttg1 signaling axis and exerts anti-PitNETs activity

Valproic acid promotes transcriptional activation of Drd2 by mediating histone acetylation to inhibit the mTOR-Pttg1 signaling axis and exerts anti-PitNETs activity

  • Phytomedicine. 2025 Jun:141:156707. doi: 10.1016/j.phymed.2025.156707.
Qiu Du 1,  Zhiyong Chen 2,  Zize Feng 3,  Yaru Li 4,  Lei Xu 4,  Yingda Lin 5,  Youwei Wang 6,  Aijun Peng 7,  Qingling Feng 8
Affiliations

Affiliations

  • 1 Department of Neurosurgery, the Affiliated Hospital of Yangzhou University, Yangzhou University No. 368 Hanjiang Middle Road, Yangzhou 225012, China; Department of Central Laboratory, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China.
  • 2 Department of Neurosurgery, the First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510632, China.
  • 3 Department of Neurosurgery, Jiangmen Central Hospital, Jiangmen 529000, China.
  • 4 Department of Central Laboratory, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou 225012, China.
  • 5 Department of Pharmacy, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China.
  • 6 Department of Neurosurgery, the Affiliated Hospital of Yangzhou University, Yangzhou University No. 368 Hanjiang Middle Road, Yangzhou 225012, China.
  • 7 Department of Neurosurgery, the Affiliated Hospital of Yangzhou University, Yangzhou University No. 368 Hanjiang Middle Road, Yangzhou 225012, China; Department of Neurosurgery, the First People's Hospital of Guannan County, Lianyungang 223500, China. Electronic address: [email protected].
  • 8 Department of Emergency Intensive Care Unit, the Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368 Hanjiang Middle Road, Yangzhou 225012, China. Electronic address: [email protected].
PMID: 40220407 DOI: 10.1016/j.phymed.2025.156707
Abstract

Background: Valproic acid (VPA), a short branched-chain fatty acid derived from valeric acid naturally produced by Valeriana officinalis L., is widely used in clinical settings for the treatment of epilepsy. Furthermore, VPA has been shown to reduce Prolactin (PRL) levels in epileptic patients and exerts anti-tumor properties. Nevertheless, the prospective anti-pituitary neuroendocrine tumors (PitNETs) effects and the underlying mechanism of VPA remain unknown.

Purpose: To assess VPA's efficacy in inhibiting PitNETs cell growth and hormone secretion, and to investigate the underlying mechanisms.

Study design/methods: The pharmacological effects of VPA in PitNETs cells were assessed using CCK-8, colony formation, EdU staining, cell cycle/Apoptosis, cell migration/invasion, and ELISA assays. The relevant VPA targets against PitNETs were assessed via RNA-sequencing and validated by qRT-PCR. CUT&RUN-qPCR was performed to detect the enrichment of DNA fragments precipitated by associated antibodies. Immunohistochemistry and western blot analysis were performed to assess the levels of factors associated with Apoptosis, cell cycle, Autophagy, and mTOR-Pttg1 signaling pathway activation.

Results: VPA significantly inhibited the proliferation, invasivity, and PRL secretion of PitNET GH3 cells, induced cytoprotective Autophagy, and also inhibited GH3-xenografted tumor growth and PRL secretion in vivo. Pretreatment with the Autophagy inhibitor significantly enhanced the inhibitory effects of VPA on GH3 cell growth and PRL secretion, and further promoted VPA-induced Apoptosis. RNA Sequencing analysis revealed 927 upregulated and 878 downregulated genes in VPA-treated GH3 cells, and the cell cycle and Other pathways were significantly enriched. Moreover, several crucial genes, including markers of proliferation Kiel 67 (Mki67), pituitary transforming gene 1 (Pttg1), and dopamine D2 receptor (Drd2), were regulated by VPA. Mechanistically, VPA induced increased histone acetylation at Drd2 promoter, activating its transcription and inhibiting the mechanistic target of the rapamycin (mTOR)-Pttg1 signaling axis. Finally, the therapeutic effects of VPA on multiple PitNET cells were evaluated and confirmed its sensitization effects on first-line therapeutics.

Conclusion: Our results revealed that VPA exerts anti-PitNET effects by promoting Drd2 transcriptional activation, thereby inhibiting the mTOR-Pttg1 signaling axis, indicating the potential therapeutic utility of VPA in PitNET treatment.

Keywords

Anti-tumor; Dopamine receptor; Histone acetylation; PitNETs; Valproic acid.

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