CHFR Regulates Chemoresistance in Triple-negative Breast Cancer Through Destabilizing ZEB1

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2021 Aug 31

PMID 34462429

Citations 7

Authors

Hong Luo

Zhicheng Zhou

Shan Huang

Mengru Ma

Manyu Zhao

Lixu Tang

Yuan Quan

Yiming Zeng

Li Su

Jongchan Kim

Peijing Zhang

Affiliations

Soon will be listed here.

Abstract

Failures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers.

Citing Articles

The effect of ribociclib on the expression levels of miR-141 and CDK4/6-USP51 signaling pathway genes in MCF-7 and MDA-MB-231 cells.

Baghermanesh S, Barati M, Hosseini A PLoS One. 2024; 19(8):e0309289.

PMID: 39196911 PMC: 11355560. DOI: 10.1371/journal.pone.0309289.

PHF12 regulates HDAC1 to promote tumorigenesis via EGFR/AKT signaling pathway in non-small cell lung cancer.

Kong Y, Jiang R, Zhou H, Ge M, Lin H, Wang Y J Transl Med. 2024; 22(1):689.

PMID: 39075515 PMC: 11287983. DOI: 10.1186/s12967-024-05488-x.

Ubiquitin-specific protease 21 promotes tumorigenicity and stemness of colorectal cancer by deubiquitinating and stabilizing ZEB1.

Lin J, Lu Y World J Gastrointest Oncol. 2024; 16(3):1006-1018.

PMID: 38577450 PMC: 10989364. DOI: 10.4251/wjgo.v16.i3.1006.

USP22 upregulates ZEB1-mediated VEGFA transcription in hepatocellular carcinoma.

Zeng K, Xie W, Wang C, Wang S, Liu W, Su Y Cell Death Dis. 2023; 14(3):194.

PMID: 36906615 PMC: 10008583. DOI: 10.1038/s41419-023-05699-y.

Epithelial-mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities.

Huang Z, Zhang Z, Zhou C, Liu L, Huang C MedComm (2020). 2022; 3(2):e144.

PMID: 35601657 PMC: 9115588. DOI: 10.1002/mco2.144.

References

Garrido-Castro A, Lin N, Polyak K . Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discov. 2019; 9(2):176-198. PMC: 6387871. DOI: 10.1158/2159-8290.CD-18-1177. View

Song X, Wu J, Yu X, Yang X, Yang Y . Trichostatin A inhibits proliferation of triple negative breast cancer cells by inducing cell cycle arrest and apoptosis. Neoplasma. 2018; 65(6):898-906. DOI: 10.4149/neo_2018_181212N476. View

Kashima L, Toyota M, Mita H, Suzuki H, Idogawa M, Ogi K . CHFR, a potential tumor suppressor, downregulates interleukin-8 through the inhibition of NF-kappaB. Oncogene. 2009; 28(29):2643-53. DOI: 10.1038/onc.2009.123. View

Zhang P, Wei Y, Wang L, Debeb B, Yuan Y, Zhang J . ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nat Cell Biol. 2014; 16(9):864-75. PMC: 4150825. DOI: 10.1038/ncb3013. View

Cortez M, Valdecanas D, Zhang X, Zhan Y, Bhardwaj V, Calin G . Therapeutic delivery of miR-200c enhances radiosensitivity in lung cancer. Mol Ther. 2014; 22(8):1494-1503. PMC: 4435581. DOI: 10.1038/mt.2014.79. View

Bianchini G, Balko J, Mayer I, Sanders M, Gianni L . Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol. 2016; 13(11):674-690. PMC: 5461122. DOI: 10.1038/nrclinonc.2016.66. View

Wellner U, Schubert J, Burk U, Schmalhofer O, Zhu F, Sonntag A . The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 2009; 11(12):1487-95. DOI: 10.1038/ncb1998. View

Kang D, Chen J, Wong J, Fang G . The checkpoint protein Chfr is a ligase that ubiquitinates Plk1 and inhibits Cdc2 at the G2 to M transition. J Cell Biol. 2002; 156(2):249-59. PMC: 2199220. DOI: 10.1083/jcb.200108016. View

Giro-Perafita A, Palomeras S, Lum D, Blancafort A, Vinas G, Oliveras G . Preclinical Evaluation of Fatty Acid Synthase and EGFR Inhibition in Triple-Negative Breast Cancer. Clin Cancer Res. 2016; 22(18):4687-97. DOI: 10.1158/1078-0432.CCR-15-3133. View

10.

Butler L, Zhou X, Xu W, Scher H, Rifkind R, Marks P . The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc Natl Acad Sci U S A. 2002; 99(18):11700-5. PMC: 129332. DOI: 10.1073/pnas.182372299. View

11.

Boumahdi S, de Sauvage F . The great escape: tumour cell plasticity in resistance to targeted therapy. Nat Rev Drug Discov. 2019; 19(1):39-56. DOI: 10.1038/s41573-019-0044-1. View

12.

Yu X, Minter-Dykhouse K, Malureanu L, Zhao W, Zhang D, Merkle C . Chfr is required for tumor suppression and Aurora A regulation. Nat Genet. 2005; 37(4):401-6. DOI: 10.1038/ng1538. View

13.

Derks S, Cleven A, Melotte V, Smits K, Brandes J, Azad N . Emerging evidence for CHFR as a cancer biomarker: from tumor biology to precision medicine. Cancer Metastasis Rev. 2013; 33(1):161-71. PMC: 3988518. DOI: 10.1007/s10555-013-9462-4. View

14.

Brabletz T, Lyden D, Steeg P, Werb Z . Roadblocks to translational advances on metastasis research. Nat Med. 2013; 19(9):1104-9. PMC: 3972758. DOI: 10.1038/nm.3327. View

15.

Zhang X, Zhang Z, Zhang Q, Zhang Q, Sun P, Xiang R . ZEB1 confers chemotherapeutic resistance to breast cancer by activating ATM. Cell Death Dis. 2018; 9(2):57. PMC: 5833408. DOI: 10.1038/s41419-017-0087-3. View

16.

Chaffer C, Marjanovic N, Lee T, Bell G, Kleer C, Reinhardt F . Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 2013; 154(1):61-74. PMC: 4015106. DOI: 10.1016/j.cell.2013.06.005. View

17.

Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M . DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene. 2005; 24(14):2375-85. DOI: 10.1038/sj.onc.1208429. View

18.

Liu C, Wu J, Paudyal S, You Z, Yu X . CHFR is important for the first wave of ubiquitination at DNA damage sites. Nucleic Acids Res. 2012; 41(3):1698-710. PMC: 3561977. DOI: 10.1093/nar/gks1278. View

19.

Satoh A, Toyota M, Itoh F, Sasaki Y, Suzuki H, Ogi K . Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer. Cancer Res. 2003; 63(24):8606-13. View

20.

Arozarena I, Wellbrock C . Phenotype plasticity as enabler of melanoma progression and therapy resistance. Nat Rev Cancer. 2019; 19(7):377-391. DOI: 10.1038/s41568-019-0154-4. View