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Dihydromyricetin induced lncRNA MALAT1-TFEB-dependent autophagic cell death in cutaneous squamous cell carcinoma
Miduo Tan1, Bin Jiang2, Haihua Wang3
1Surgery Department of Galactophore, The Affiliated Zhuzhou Hospital of Xiangya Medical College CSU, Zhuzhou 412000, China.
Abstract:
Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer. Dihydromyricetin (DHM), a Rattan tea extract, has been shown to have antitumor activity with no obvious toxicity to normal cells in vitro and in vivo. However, its efficacy in the treatment of CSCC and the underlying antitumor mechanism has not been fully elucidated yet. In our study, DHM increased autophagic flux in the A431 cells, as evidenced by the upregulation of LC3-II and downregulation of P62/SQSTM1. Moreover, the pharmacological or genetic blocking autophagy decreased DHM-induced cell death, indicating DHM triggered autophagic cell death in A431 cells. Specifically, DHM induced TFEB(Ser142) de-phosphorylation, activated TFEB nuclear translocation and increased of TFEB reporter activity, which contributed to the expression of autophagy-related genes and subsequent initiated autophagic cell death in A431 cells. Importantly, DHM decreased lncRNA MALAT1 expression and MALAT1 overexpression abrogated the effects of DHM on TFEB-dependent autophagy both in vitro and in vivo. Taken together, DHM induces CSCC cell death via inducing excessive autophagy, which is mediated through the MALAT1-TFEB pathway. Therefore, DHM may be beneficial for the development of chemotherapy for CSCC.
Insights
Dihydromyricetin (DHM) triggers cancer cell death in cutaneous squamous cell carcinoma (CSCC) by inducing excessive autophagy through the MALAT1-TFEB pathway. This finding suggests DHM
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Cutaneous squamous cell carcinoma (CSCC) is a prevalent skin cancer.
- Dihydromyricetin (DHM), a natural compound, exhibits antitumor properties.
- The precise mechanism of DHM's action in CSCC requires further investigation.
Purpose of the Study:
- To elucidate the antitumor mechanism of DHM in CSCC.
- To investigate DHM's effect on autophagy and related pathways in CSCC cells.
- To determine the role of MALAT1 and TFEB in DHM-induced cell death.
Main Methods:
- Assessed autophagic flux using LC3-II and P62/SQSTM1 markers in A431 cells.
- Investigated DHM's impact on TFEB phosphorylation, nuclear translocation, and reporter activity.
- Examined the role of MALAT1 in DHM-mediated autophagy and cell death via overexpression studies.
- Utilized pharmacological and genetic autophagy inhibition to assess DHM's effects.
Main Results:
- DHM significantly increased autophagic flux in A431 cells.
- Autophagy inhibition reduced DHM-induced cell death, confirming autophagic cell death.
- DHM de-phosphorylated TFEB at Ser142, promoting its nuclear translocation and activating autophagy-related gene expression.
- DHM decreased MALAT1 expression, while MALAT1 overexpression counteracted DHM's effects on TFEB-dependent autophagy.
Conclusions:
- DHM induces autophagic cell death in CSCC through the MALAT1-TFEB pathway.
- DHM's mechanism involves activating TFEB-dependent autophagy by downregulating MALAT1.
- Dihydromyricetin shows potential as a therapeutic agent for cutaneous squamous cell carcinoma.
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