Huaier Inhibits Proliferation, Migration, and Invasion of Cutaneous Squamous Cell Carcinoma Cells by Inhibiting the Methylation Levels of CDKN2A and TP53

Overview

Journal Integr Cancer Ther

Publisher Sage Publications

Specialties Oncology
Pharmacology

Date 2021 Jul 22

PMID 34291682

Citations 2

Authors

Liang Wang

Lei Xu

Yu Wang

Affiliations

Soon will be listed here.

Abstract

Cutaneous squamous cell carcinoma (CSCC) is a malignant tumor that originates from keratinocytes in the epidermis or appendage. Traditional Chinese medicine Huaier has anti-tumor activity in various malignancies. Little is known about the role of Huaier in CSCC. Here, we investigated the function of Huaier in CSCC. We treated CSCC cell line (SCL-1 and A431) with a series of concentration gradients of Huaier to examine the half maximal inhibitory concentration (IC50) of Huaier on SCL-1 and A431 cells. The IC50 of Huaier on growth of SCL-1 and A431 cells were 6.96 and 7.57 mg/mL, respectively. Moreover, Huaier reduced the methylation levels of CDKN2A and TP53, and enhanced the expression of CDKN2A and TP53 in SCL-1 and A431 cells in a dosage-dependent manner. The expression of DNA methyltransferase DNMT1 was severely repressed by Huaier treatment in SCL-1 and A431 cells. DNMT1 overexpression enhanced the methylation levels of CDKN2A and TP53, and suppressed the expression of CDKN2A and TP53 in Huaier-treated SCL-1 and A431 cells. Huaier treatment inhibited proliferation, migration, and invasion of SCL-1 and A431 cells. However, inhibition of CDKN2A or TP53 reversed the influence of Huaier treatment on proliferation, migration, and invasion of CSCC cells. In conclusion, our data demonstrate that Huaier inhibits proliferation, migration, and invasion of CSCC cells by regulating DNA methylation of CDKN2A and TP53, thereby attenuating the progression of CSCC. Thus, Huaier extract may act as a drug for treating CSCC.

Citing Articles

Overexpression of lncRNA TINCR inhibits cutaneous squamous cell carcinoma cells through promotes methylation of Myc and TERC genes.

Wang L, Wang Y, Xu L Arch Dermatol Res. 2025; 317(1):559.

PMID: 40072633 PMC: 11903621. DOI: 10.1007/s00403-025-03964-y.

Wang Y, Pan K, Chen M Discov Oncol. 2023; 14(1):192.

PMID: 37878133 PMC: 10600093. DOI: 10.1007/s12672-023-00794-0.

A network pharmacology-based exploration of the active compounds and potential drug targets of Si-Jun-Zi decoction in the treatment of cutaneous squamous cell carcinoma.

Qin S, Zhang L, Zhang H, Shi S, Zhou X, Lu Z Transl Cancer Res. 2022; 11(8):2887-2901.

PMID: 36093517 PMC: 9459502. DOI: 10.21037/tcr-22-1716.

References

Venza M, Visalli M, Catalano T, Beninati C, Teti D, Venza I . DSS1 promoter hypomethylation and overexpression predict poor prognosis in melanoma and squamous cell carcinoma patients. Hum Pathol. 2016; 60:137-146. DOI: 10.1016/j.humpath.2016.10.018. View

Jiao Y, Feng Y, Wang X . Regulation of Tumor Suppressor Gene CDKN2A and Encoded p16-INK4a Protein by Covalent Modifications. Biochemistry (Mosc). 2018; 83(11):1289-1298. DOI: 10.1134/S0006297918110019. View

Xu D, Yuan X, Hirayama M, Toyoda H . Huaier Extract Induces Apoptosis in Hepatoblastoma Cells the MEK/ERK Signaling Pathway. In Vivo. 2020; 34(5):2381-2388. PMC: 7652502. DOI: 10.21873/invivo.12051. View

Inman G, Wang J, Nagano A, Alexandrov L, Purdie K, Taylor R . The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature. Nat Commun. 2018; 9(1):3667. PMC: 6131170. DOI: 10.1038/s41467-018-06027-1. View

de Oliveira D, Savio A, de Castro Marcondes J, Barros T, Barbosa L, Salvadori D . Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status. J Biosci. 2017; 42(1):91-101. DOI: 10.1007/s12038-016-9654-5. View

Aubrey B, Strasser A, Kelly G . Tumor-Suppressor Functions of the TP53 Pathway. Cold Spring Harb Perspect Med. 2016; 6(5). PMC: 4852799. DOI: 10.1101/cshperspect.a026062. View

Li L, Jiang M, Feng Q, Kiviat N, Stern J, Hawes S . Aberrant Methylation Changes Detected in Cutaneous Squamous Cell Carcinoma of Immunocompetent Individuals. Cell Biochem Biophys. 2015; 72(2):599-604. DOI: 10.1007/s12013-014-0507-2. View

Yagi M, Kabata M, Tanaka A, Ukai T, Ohta S, Nakabayashi K . Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development. Nat Commun. 2020; 11(1):3199. PMC: 7314859. DOI: 10.1038/s41467-020-16989-w. View

Al-Rohil R, Tarasen A, Carlson J, Wang K, Johnson A, Yelensky R . Evaluation of 122 advanced-stage cutaneous squamous cell carcinomas by comprehensive genomic profiling opens the door for new routes to targeted therapies. Cancer. 2015; 122(2):249-57. DOI: 10.1002/cncr.29738. View

10.

Yang A, Zhao Y, Wang Y, Zha X, Zhao Y, Tu P . Huaier suppresses proliferative and metastatic potential of prostate cancer PC3 cells via downregulation of Lamin B1 and induction of autophagy. Oncol Rep. 2018; 39(6):3055-3063. DOI: 10.3892/or.2018.6358. View

11.

Su D, Jiang B, Yang Y, Miao Y, Fu Q, Zhang F . Effect of Huaier on Melanoma Invasion, Metastasis, and Angiogenesis. Biomed Res Int. 2020; 2020:8163839. PMC: 7298256. DOI: 10.1155/2020/8163839. View

12.

Yanagi T, Watanabe M, Hata H, Kitamura S, Imafuku K, Yanagi H . Loss of TRIM29 Alters Keratin Distribution to Promote Cell Invasion in Squamous Cell Carcinoma. Cancer Res. 2018; 78(24):6795-6806. DOI: 10.1158/0008-5472.CAN-18-1495. View

13.

Hervas-Marin D, Higgins F, Sanmartin O, Lopez-Guerrero J, Bano M, Igual J . Genome wide DNA methylation profiling identifies specific epigenetic features in high-risk cutaneous squamous cell carcinoma. PLoS One. 2019; 14(12):e0223341. PMC: 6924689. DOI: 10.1371/journal.pone.0223341. View

14.

Toll A, Salgado R, Espinet B, Diaz-Lagares A, Hernandez-Ruiz E, Andrades E . MiR-204 silencing in intraepithelial to invasive cutaneous squamous cell carcinoma progression. Mol Cancer. 2016; 15(1):53. PMC: 4960761. DOI: 10.1186/s12943-016-0537-z. View

15.

Padhi S, Roy S, Kar M, Saha A, Roy S, Adhya A . Role of CDKN2A/p16 expression in the prognostication of oral squamous cell carcinoma. Oral Oncol. 2017; 73:27-35. DOI: 10.1016/j.oraloncology.2017.07.030. View

16.

Chen Y, Wu H, Wang X, Wang C, Gan L, Zhu J . Huaier Granule extract inhibit the proliferation and metastasis of lung cancer cells through down-regulation of MTDH, JAK2/STAT3 and MAPK signaling pathways. Biomed Pharmacother. 2018; 101:311-321. DOI: 10.1016/j.biopha.2018.02.028. View

17.

Gao S, Li X, Ding X, Jiang L, Yang Q . Huaier extract restrains the proliferative potential of endocrine-resistant breast cancer cells through increased ATM by suppressing miR-203. Sci Rep. 2017; 7(1):7313. PMC: 5544732. DOI: 10.1038/s41598-017-07550-9. View

18.

Li L, Li F, Xia Y, Yang X, Lv Q, Fang F . UVB induces cutaneous squamous cell carcinoma progression by de novo ID4 methylation via methylation regulating enzymes. EBioMedicine. 2020; 57:102835. PMC: 7317242. DOI: 10.1016/j.ebiom.2020.102835. View

19.

Que S, Zwald F, Schmults C . Cutaneous squamous cell carcinoma: Incidence, risk factors, diagnosis, and staging. J Am Acad Dermatol. 2018; 78(2):237-247. DOI: 10.1016/j.jaad.2017.08.059. View

20.

Zhao R, Choi B, Lee M, Bode A, Dong Z . Implications of Genetic and Epigenetic Alterations of CDKN2A (p16(INK4a)) in Cancer. EBioMedicine. 2016; 8:30-39. PMC: 4919535. DOI: 10.1016/j.ebiom.2016.04.017. View