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Targeting G-rich sequence to regulate the transcription of murine double minute (MDM) genes in triple-negative breast
Yuxin Feng1, Xuan Xuan1, Yuemiao Hu1
1School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China.
Abstract:
Murine double minute 2 (MDM2) and homologous protein murine double minute X (MDMX) are p53 negative regulators that perform significant driving effects in tumorigenesis, and targeting these oncoproteins has became an efficient strategy in treating cancers. However, the definite antitumor activity and significance ordering of each protein in MDM family is still unclear due to the similar structure and complicated regulation. Herein, we identified two G-rich sequences (G1 and G5) located in the promoter that could assemble the G-quadruplex to respectively inhibit and promote the transcription of the MDM2 and MDMX. Based on this target, we designed and synthesized a novel G-quadruplex ligand A3f and achieved the differentiated regulation of MDM protein. In triple-negative breast cancer (TNBC) cells, A3f could induce MDM2-dependent proliferation arrest and exhibit additive therapeutic effect with MDMX inhibitors. Overall, this study provided a novel strategy to regulate the transcription of MDM genes by targeting certain G-rich sequences, and discovered an active antitumor molecule for use in TNBC treatment.
Insights
Researchers identified G-rich sequences in gene promoters that regulate murine double minute 2 (MDM2) and murine double minute X (MDMX) transcription. A novel G-quadruplex ligand, A3f, demonstrated antitumor activity in triple-negative breast cancer cells.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- Murine double minute 2 (MDM2) and murine double minute X (MDMX) are key negative regulators of the p53 tumor suppressor.
- Dysregulation of MDM2 and MDMX contributes significantly to tumorigenesis.
- Targeting MDM proteins is a promising cancer therapy strategy, but their complex regulation requires further investigation.
Purpose of the Study:
- To identify novel regulatory elements within the MDM gene promoters.
- To design and synthesize a G-quadruplex ligand for differentiated regulation of MDM2 and MDMX.
- To evaluate the therapeutic potential of the novel ligand in triple-negative breast cancer (TNBC).
Main Methods:
- Identification of G-rich sequences (G1 and G5) in MDM2 and MDMX promoters capable of forming G-quadruplex structures.
- Design and synthesis of a novel G-quadruplex ligand, A3f.
- Assessment of A3f's effect on MDM2 and MDMX transcription and TNBC cell proliferation.
- Evaluation of combination therapy with MDMX inhibitors.
Main Results:
- Two G-rich sequences (G1 and G5) were identified in the MDM2 and MDMX promoters, respectively, which form G-quadruplexes.
- The synthesized G-quadruplex ligand A3f demonstrated differentiated regulation of MDM2 and MDMX transcription.
- A3f induced MDM2-dependent proliferation arrest in TNBC cells.
- A3f exhibited an additive therapeutic effect when combined with MDMX inhibitors.
Conclusions:
- Targeting specific G-quadruplex sequences in gene promoters offers a novel strategy for regulating MDM gene transcription.
- The novel G-quadruplex ligand A3f shows significant antitumor activity in TNBC.
- A3f represents a potential therapeutic candidate for TNBC treatment, possibly in combination therapies.
