ANKHD1 is Required for SMYD3 to Promote Tumor Metastasis in Hepatocellular Carcinoma

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2019 Jan 17

PMID 30646949

Citations 23

Authors

Zhenyu Zhou

Hai Jiang

Kangsheng Tu

Wei Yu

Jianlong Zhang

ZhiGang Hu

Heyun Zhang

Dake Hao

Pinbo Huang

Jie Wang

Aijun Wang

Zhiyu Xiao

Chuanchao He

Affiliations

Soon will be listed here.

Abstract

Absract: BACKGROUND: Tumor metastasis is the major reason for poor prognosis of hepatocellular carcinoma (HCC) patients after hepatic resection. SMYD3 has been demonstrated to promote liver tumor metastasis in mice. However, the detailed molecular mechanism is still largely unknown.

Methods: The effect of SMYD3 on invasiveness and metastasis of HCC was analyzed by immunohistochemistry, migration assay, invasion assay, wound healing assay and in vivo lung metastasis assay. Mass spectrometry analysis was conducted using proteins pulled down by H3K4me3 antibody in SMYD3-overexpressing cells. Luciferase reporter, chromatin immunoprecipitation, Electrophoretic mobility shift assay were used to measure the regulation of SLUG transcription by SMYD3-ANKHD1. In addition, the role of SMYD3-ANKHD1 in determining clinical outcomes for HCC patients was investigated by immunohistochemistry in 243 HCC tissues.

Results: SMYD3 was an independent prognostic factor of HCC and promoted migration and invasion of human HCC cells. ANKHD1 was identified by mass spectrometry as a co-regulator with SMYD3. ANKHD1 interacted with H3K4me3 when cells were overexpressing SMYD3. The pro-migratory and pro-invasive effects of SMYD3 were attenuated when ANKHD1 was knocked down by siRNA. Furthermore, we found that SMYD3 bound and activated the SLUG gene promoter in a manner associated with elevating H3K4me3, H3K9Ac and H3K14Ac. Knockdown of ANKHD1 could attenuate the SMYD3-dependent activation of Slug expression. We further detected the expression of SMYD3 and ANKHD1 in 243 HCC patients and found that patients with positive coexpression of SMYD3 and ANKHD1 (SMYD3ANKHD1) had the shortest overall and recurrence-free survival.

Conclusion: Our findings provide a novel molecular mechanism for the SMYD3-regulated HCC migration and metastasis, and indicates that SMYD3-ANKHD1 may be a potential target for treating HCC.

Citing Articles

SMYD family in cancer: epigenetic regulation and molecular mechanisms of cancer proliferation, metastasis, and drug resistance.

Han T, Kim D, Son M, Cho H Exp Mol Med. 2024; 56(11):2325-2336.

PMID: 39482529 PMC: 11611910. DOI: 10.1038/s12276-024-01326-8.

SMYD4 monomethylates PRMT5 and forms a positive feedback loop to promote hepatocellular carcinoma progression.

Zhou Z, Chen Z, Zhou Q, Meng S, Shi J, Mui S Cancer Sci. 2024; 115(5):1587-1601.

PMID: 38438251 PMC: 11093212. DOI: 10.1111/cas.16139.

Evaluating the Molecular Properties and Function of ANKHD1, and Its Role in Cancer.

Mullenger J, Zeidler M, Fragiadaki M Int J Mol Sci. 2023; 24(16).

PMID: 37629022 PMC: 10454556. DOI: 10.3390/ijms241612834.

SMYD3 induces sorafenib resistance by activating SMAD2/3-mediated epithelial-mesenchymal transition in hepatocellular carcinoma.

Wang S, You X, Liu X, Zhang F, Zhou H, Shang X iScience. 2023; 26(7):106994.

PMID: 37534166 PMC: 10391607. DOI: 10.1016/j.isci.2023.106994.

SMYD Family Members Serve as Potential Prognostic Markers and Correlate with Immune Infiltrates in Gastric Cancer.

Liu D, Liu M, Wang W, Li X, Shi E, Zhang C J Oncol. 2023; 2023:6032864.

PMID: 36816359 PMC: 9929213. DOI: 10.1155/2023/6032864.

References

Smith R, Carroll P, Allard J, Simon M . MASK, a large ankyrin repeat and KH domain-containing protein involved in Drosophila receptor tyrosine kinase signaling. Development. 2002; 129(1):71-82. DOI: 10.1242/dev.129.1.71. View

Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva F, Li M . SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol. 2004; 6(8):731-40. DOI: 10.1038/ncb1151. View

Ruthenburg A, Allis C, Wysocka J . Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell. 2007; 25(1):15-30. DOI: 10.1016/j.molcel.2006.12.014. View

Collins R, Northrop J, Horton J, Lee D, Zhang X, Stallcup M . The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and dimethyllysine binding modules. Nat Struct Mol Biol. 2008; 15(3):245-50. PMC: 2586904. DOI: 10.1038/nsmb.1384. View

Cock-Rada A, Medjkane S, Janski N, Yousfi N, Perichon M, Chaussepied M . SMYD3 promotes cancer invasion by epigenetic upregulation of the metalloproteinase MMP-9. Cancer Res. 2011; 72(3):810-20. PMC: 3299564. DOI: 10.1158/0008-5472.CAN-11-1052. View

Van Aller G, Reynoird N, Barbash O, Huddleston M, Liu S, Zmoos A . Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation. Epigenetics. 2012; 7(4):340-3. PMC: 3368817. DOI: 10.4161/epi.19506. View

Musselman C, Lalonde M, Cote J, Kutateladze T . Perceiving the epigenetic landscape through histone readers. Nat Struct Mol Biol. 2012; 19(12):1218-27. PMC: 3645987. DOI: 10.1038/nsmb.2436. View

Sansores-Garcia L, Atkins M, Moya I, Shahmoradgoli M, Tao C, Mills G . Mask is required for the activity of the Hippo pathway effector Yki/YAP. Curr Biol. 2013; 23(3):229-35. PMC: 4089957. DOI: 10.1016/j.cub.2012.12.033. View

Machado-Neto J, Lazarini M, Favaro P, Franchi Jr G, Nowill A, Olalla Saad S . ANKHD1, a novel component of the Hippo signaling pathway, promotes YAP1 activation and cell cycle progression in prostate cancer cells. Exp Cell Res. 2014; 324(2):137-45. DOI: 10.1016/j.yexcr.2014.04.004. View

10.

Tabrizian P, Jibara G, Shrager B, Schwartz M, Roayaie S . Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann Surg. 2014; 261(5):947-55. DOI: 10.1097/SLA.0000000000000710. View

11.

Hirokawa F, Kubo S, Nagano H, Nakai T, Kaibori M, Hayashi M . Do patients with small solitary hepatocellular carcinomas without macroscopically vascular invasion require anatomic resection? Propensity score analysis. Surgery. 2014; 157(1):27-36. DOI: 10.1016/j.surg.2014.06.080. View

12.

Machado-Neto J, Lazarini M, Favaro P, Campos P, Scopim-Ribeiro R, Franchi Junior G . ANKHD1 silencing inhibits Stathmin 1 activity, cell proliferation and migration of leukemia cells. Biochim Biophys Acta. 2014; 1853(3):583-93. DOI: 10.1016/j.bbamcr.2014.12.012. View

13.

Mozzetta C, Boyarchuk E, Pontis J, Ait-Si-Ali S . Sound of silence: the properties and functions of repressive Lys methyltransferases. Nat Rev Mol Cell Biol. 2015; 16(8):499-513. DOI: 10.1038/nrm4029. View

14.

Sarris M, Moulos P, Haroniti A, Giakountis A, Talianidis I . Smyd3 Is a Transcriptional Potentiator of Multiple Cancer-Promoting Genes and Required for Liver and Colon Cancer Development. Cancer Cell. 2016; 29(3):354-366. DOI: 10.1016/j.ccell.2016.01.013. View

15.

Allis C, Jenuwein T . The molecular hallmarks of epigenetic control. Nat Rev Genet. 2016; 17(8):487-500. DOI: 10.1038/nrg.2016.59. View

16.

Andrews F, Strahl B, Kutateladze T . Insights into newly discovered marks and readers of epigenetic information. Nat Chem Biol. 2016; 12(9):662-8. PMC: 5116920. DOI: 10.1038/nchembio.2149. View

17.

Giakountis A, Moulos P, Sarris M, Hatzis P, Talianidis I . Smyd3-associated regulatory pathways in cancer. Semin Cancer Biol. 2016; 42:70-80. DOI: 10.1016/j.semcancer.2016.08.008. View

18.

Tsai C, Chen Y, Yu C, Tzeng S, Wu I, Kuo W . SMYD3-Mediated H2A.Z.1 Methylation Promotes Cell Cycle and Cancer Proliferation. Cancer Res. 2016; 76(20):6043-6053. DOI: 10.1158/0008-5472.CAN-16-0500. View

19.

Yoshioka Y, Suzuki T, Matsuo Y, Nakakido M, Tsurita G, Simone C . SMYD3-mediated lysine methylation in the PH domain is critical for activation of AKT1. Oncotarget. 2016; 7(46):75023-75037. PMC: 5342720. DOI: 10.18632/oncotarget.11898. View

20.

Hyun K, Jeon J, Park K, Kim J . Writing, erasing and reading histone lysine methylations. Exp Mol Med. 2017; 49(4):e324. PMC: 6130214. DOI: 10.1038/emm.2017.11. View