Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Aug 12:8:724.
doi: 10.3389/fcell.2020.00724. eCollection 2020.

Promoter Hypomethylation and miR-145-5p Downregulation- Mediated HDAC11 Overexpression Promotes Sorafenib Resistance and Metastasis of Hepatocellular Carcinoma Cells

Wenlong Wang  1 , Bisha Ding  2 , Weiyang Lou  3 , Shengyou Lin  4
Affiliations

Promoter Hypomethylation and miR-145-5p Downregulation- Mediated HDAC11 Overexpression Promotes Sorafenib Resistance and Metastasis of Hepatocellular Carcinoma Cells

Wenlong Wang et al. Front Cell Dev Biol. .

Abstract

Sorafenib resistance and tumor metastasis account for poor outcome of hepatocellular carcinoma (HCC). Histone deacetylase 11 (HDAC11) has been reported to exert oncogenic effects in several types of human cancer, but its specific functions and detailed mechanisms in HCC are not fully elucidated. Here we identified HDAC11 as a potential oncogene and promising biomarker in HCC by in silico analysis. Histone deacetylase 11 was upregulated in sorafenib-resistant SMMC7721 compared with its parental cell. Knockdown of HDAC11 suppressed proliferation and sorafenib resistance, which may be due to inhibition of drug metabolism cytochrome P450 predicted by gene-set enrichment analysis. Histone deacetylase expression was higher in highly metastatic MHCC97H than lowly metastatic MHCC97L. Downregulation of HDAC11 significantly attenuated the migrated and invaded abilities of HCC cells. Histone deacetylase 11 was directly targeted and suppressed by miR-145-5p. Inhibition of miR-145-5p enhanced sorafenib resistance and metastasis of HCC, and these effects could be attenuated by knockdown of HDAC11. The promoter methylation level of HDAC11 was markedly decreased in HCC tissues compared with normal controls. Administration of 5'-Aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, facilitated HDAC11 expression in HCC cells. Our data indicate a role of miR-145-5p/HDAC11 axis in regulation of sorafenib resistance and metastasis in HCC.

Keywords: HDAC11; hepatocellular carcinoma; metastasis; methylation; miR-145-5p; sorafenib resistance.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
The expression levels of HDAC family members in TCGA HCC tissues compared with TCGA normal liver tissues. (A) HDAC1. (B) HDAC2. (C) HDAC3. (D) HDAC8. (E) HDAC4. (F) HDAC5. (G) HDAC7. (H) HDAC9. (I) HDAC6. (J) HDAC10. (K) HDAC11. TCGA, The Cancer Genome Atlas. *P < 0.05.
FIGURE 2
FIGURE 2
The diagnostic values of HDAC family members in TCGA HCC. (A) HDAC1. (B) HDAC2. (C) HDAC3. (D) HDAC8. (E) HDAC4. (F) HDAC5. (G) HDAC7. (H) HDAC9. (I) HDAC6. (J) HDAC10. (K) HDAC11.
FIGURE 3
FIGURE 3
The prognostic values (overall survival) of HDAC family members in TCGA HCC. (A) HDAC1. (B) HDAC2. (C) HDAC3. (D) HDAC8. (E) HDAC4. (F) HDAC5. (G) HDAC7. (H) HDAC9. (I) HDAC6. (J) HDAC10. (K) HDAC11.
FIGURE 4
FIGURE 4
Knockdown of HDAC11 suppressed sorafenib resistance of HCC in vitro. (A) High expression of HDAC11 indicated poor prognosis in sorafenib-treated HCC from TCGA database. (B,C) HDAC11 mRNA and protein were significantly upregulated in SMMC7721/SR compared with SMMC7721. (D,E) HDAC11 expression was markedly decreased after treatment of siRNAs targeting HDAC11. (F,G) Inhibition of HDAC11 suppressed sorafenib resistance of SMMC7721. (H,I) Inhibition of HDAC11 suppressed sorafenib resistance of SMMC7721/SR. (J,K) Inhibition of HDAC11 attenuated colony formation of HCC cells. (L) GSEA suggested that drug metabolism cytochrome P450 pathway was significantly enriched in HDAC11-low expression group. *P < 0.05, **P < 0.01, ***P < 0.001.
FIGURE 5
FIGURE 5
Knockdown of HDAC11 suppressed metastasis of HCC in vitro. (A) High expression of HDAC11 indicated poor prognosis in HCC with vascular invasion from TCGA database. (B,C) HDAC11 mRNA and protein were significantly upregulated in MHCC97H compared with MHCC97L. (D) Inhibition of HDAC11 markedly suppressed migration of MHCC97L cell. (E) Inhibition of HDAC11 markedly suppressed migration of MHCC97H cell. (F,G) Inhibition of HDAC11 markedly suppressed invasion of MHCC97L cell. (H,I) Inhibition of HDAC11 markedly suppressed invasion of MHCC97L cell. **P < 0.01, ***P < 0.001.
FIGURE 6
FIGURE 6
miR-145-5p targeted HDAC11 and repressed sorafenib resistance and metastasis of HCC in vitro. (A) The expression correlation of HDAC11 and miR-145-5p in HCC determined by starBase. (B) miR-145-5p expression was significantly downregulated in HCC tissues compared with normal liver tissues determined by starBase. (C) HCC patients with higher expression of miR-145-5p indicated poorer prognosis determined by Kaplan–Meier plotter. (D) miR-145-5p expression was markedly decreased in HCC cell lines compared with normal liver cell. (E) Dual luciferase reporter assay confirmed the direct bind between miR-145-5p and HDAC11. (F) miR-145-5p upregulation significantly decreased HDAC11 expression, whereas miR-145-5p inhibition increased HDAC11 expression in HCC. (G) miR-145-5p inhibition increased HCC cell resistance to sorafenib, and this effect can be reversed after knockdown of HDAC11. (H) miR-145-5p inhibition promoted HCC cell colony formation, and this effect can be reversed after knockdown of HDAC11. (I) miR-145-5p inhibition promoted HCC cell migration, and this effect can be reversed after knockdown of HDAC11. 48 h after wounding. (J) miR-145-5p inhibition promoted HCC cell invasion, and this effect can be reversed after knockdown of HDAC11. *P < 0.05, **P < 0.01, ***P < 0.001.
FIGURE 7
FIGURE 7
Promoter hypomethylation was responsible for HDAC11 overexpression in HCC. (A,B) HDAC11 was upregulated, whereas its promoter methylation level was downregulated in all HCC samples compared with normal controls. (C,D) HDAC11 was upregulated, whereas its promoter methylation level was downregulated in HCC based on tumor grade. (E,F) HDAC11 was upregulated, whereas its promoter methylation level was downregulated in HCC based on individual cancer stages. (G,H) HDAC11 was upregulated, whereas its promoter methylation level was downregulated in HCC based on nodal metastasis status. (I) The expression of HDAC11 was significantly increased after treatment of DNA methyltransferase inhibitor 5’-Aza-2’-deoxycytidine in SMMC7721. (J) The expression of HDAC11 was significantly increased after treatment of DNA methyltransferase inhibitor 5’-Aza-2’-deoxycytidine in SMMC7721/SR. (K) The expression of HDAC11 was significantly increased after treatment of DNA methyltransferase inhibitor 5’-Aza-2’-deoxycytidine in MHCC97L. (L) The expression of HDAC11 was significantly increased after treatment of DNA methyltransferase inhibitor 5’-Aza-2’-deoxycytidine in MHCC97H. *P < 0.05, **P < 0.01, ***P < 0.001.
FIGURE 8
FIGURE 8
The model of promoter hypomethylation/miR-145-5p/HDAC11 axis in regulation of sorafenib resistance and metastasis of HCC.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Almazroo O. A., Miah M. K., Venkataramanan R. (2017). Drug metabolism in the liver. Clin. Liver Dis. 21 1–20. - PubMed
    1. Bray F., Ferlay J., Soerjomataram I., Siegel R. L., Torre L. A., Jemal A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68 394–424. 10.3322/caac.21492 - DOI - PubMed
    1. Chandrashekar D. S., Bashel B., Balasubramanya S. A. H., Creighton C. J., Ponce-Rodriguez I., Chakravarthi B., et al. (2017). UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 19 649–658. 10.1016/j.neo.2017.05.002 - DOI - PMC - PubMed
    1. Chen J., Chen T., Zhu Y., Li Y., Zhang Y., Wang Y., et al. (2019). circPTN sponges miR-145-5p/miR-330-5p to promote proliferation and stemness in glioma. J. Exp. Clin. Cancer Res. 38:398. - PMC - PubMed
    1. Chen Q., Zhou L., Ye X., Tao M., Wu J. (2020). miR-145-5p suppresses proliferation, metastasis and EMT of colorectal cancer by targeting CDCA3. Pathol. Res. Pract. 216:152872. 10.1016/j.prp.2020.152872 - DOI - PubMed

LinkOut - more resources