2. Academic Validation
  3. Bifunctional HDAC and DNMT inhibitor induces viral mimicry activates the innate immune response in triple-negative breast cancer

Bifunctional HDAC and DNMT inhibitor induces viral mimicry activates the innate immune response in triple-negative breast cancer

  • Eur J Pharm Sci. 2024 Jun 1:197:106767. doi: 10.1016/j.ejps.2024.106767.
Weiwen Fan 1,  Wenkai Li 1,  Lulu Li 2,  Meirong Qin 3,  Chengzhou Mao 4,  Zigao Yuan 2,  Ping Wang 5,  Bizhu Chu 6,  Yuyang Jiang 7
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
  • 2 State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China.
  • 3 Shenzhen Institute for Drug Control, Shenzhen 518057, China.
  • 4 Department of Anatomy and Histology, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China.
  • 5 Shenzhen Institute for Drug Control, Shenzhen 518057, China. Electronic address: wangping662@sina.com.
  • 6 Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China. Electronic address: chubz@szu.edu.cn.
  • 7 Guangdong Provincial Key Laboratory of Chinese Medicine Ingredients and Gut Microbiomics, School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China; State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
PMID: 38636781 DOI: 10.1016/j.ejps.2024.106767
Abstract

Triple-negative breast Cancer (TNBC) is a unique breast Cancer subtype characterized by a lack of Estrogen Receptor (ER), Progesterone Receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Since TNBC lacks ER, PR, and HER2, there are currently no drugs that specifically target TNBC. Therefore, the development of new drugs or effective treatment strategies to target TNBC has become an urgent clinical need. Research has shown that the application of histone deacetylase (HDAC) inhibitors and DNA Methyltransferase (DNMT) inhibitors leads to genomic and epigenomic instability. This, in turn, triggers the activation of Pattern Recognition Receptors (PRRs) and subsequently activates downstream interferon (IFN) signalling pathways. In this study, the bifunctional HDAC and DNMT inhibitor J208 exhibited antitumour activity in TNBC cell lines. J208 effectively induced Apoptosis and cell cycle arrest at the G0/G1 phase, inhibiting cell migration and invasion in TNBC. Moreover, this bifunctional inhibitor induced the expression of endogenous retroviruses (ERVs) and elicited a viral mimicry response, which increased the intracellular levels of double-stranded RNA (dsRNA) to activate the innate immune signalling pathway in TNBC. In summary, we demonstrated that the bifunctional inhibitor J208, which is designed to inhibit HDAC and DNMT, has potent Anticancer effects, providing a new research basis for reactivating antitumour immunity by triggering innate immune signalling and offering a promising strategy for TNBC treatment.

Keywords

Bifunctional inhibitor; Dnmt; Hdac; Innate immunity; Viral mimicry.

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