Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis

Abstract Background Recent studies suggested that ZMYND10 is a potential tumor suppressor gene in multiple tumor types. However, the mechanism by which ZMYND10 inhibits breast cancer remains unclear. Here, we investigated the role and mechanism of ZMYND10 in breast cancer inhibition. Results ZMYND10 was dramatically reduced in multiple breast cancer cell lines and tissues, which was associated with promoter hypermethylation. Ectopic expression of ZMYND10 in silenced breast cancer cells induced cell apoptosis while suppressed cell growth, cell migration and invasion in vitro, and xenograft tumor growth in vivo. Furthermore, molecular mechanism studies indicated that ZMYND10 enhances expression of miR145-5p, which suppresses the expression of NEDD9 protein through directly targeting the 3'-untranslated region of NEDD9 mRNA. Conclusions Results from this study show that ZMYND10 suppresses breast cancer tumorigenicity by inhibiting the miR145-5p/NEDD9 signaling pathway. This novel discovered signaling pathway may be a valid target for small molecules that might help to develop new therapies to better inhibit the breast cancer metastasis.

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Genome-wide CRISPR/Cas9 knockout screening uncovers ZNF319 as a novel tumor suppressor critical for breast cancer metastasis

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2021.12.023 ◽

2021 ◽

Author(s):

Longlong Wang ◽

Lijun Zhou ◽

Miao Li ◽

Jin Zhao ◽

Yanhua Liu ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Genome Wide

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Multiple steps in carcinogenesis involving alterations of multiple tumor suppressor genes

The FASEB Journal ◽

10.1096/fasebj.7.10.8344488 ◽

1993 ◽

Vol 7 (10) ◽

pp. 920-925 ◽

Cited By ~ 65

Author(s):

Jun Yokota ◽

Takashi Sugimura

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

Suppressor Genes ◽

Multiple Tumor

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Regulation of deleted in liver cancer 1 tumor suppressor by protein-protein interactions and phosphorylation

International Journal of Cancer ◽

10.1002/ijc.28505 ◽

2013 ◽

Vol 135 (2) ◽

pp. 264-269 ◽

Cited By ~ 13

Author(s):

Frankie Chi Fat Ko ◽

Judy Wai Ping Yam

Keyword(s):

Tumor Suppressor ◽

Liver Cancer ◽

Protein Interactions ◽

Protein Protein Interactions

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Quantitative study on expression of p16 multiple tumor suppressor gene in salivary gland neoplasm

Journal of Tongji Medical University ◽

10.1007/bf02886899 ◽

1999 ◽

Vol 19 (2) ◽

pp. 155-157 ◽

Cited By ~ 3

Author(s):

Zhu Shengrong ◽

Wang Xiuli ◽

Shao Lenan ◽

Chen Weimin ◽

Chen Xinming ◽

...

Keyword(s):

Salivary Gland ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Quantitative Study ◽

Suppressor Gene ◽

Salivary Gland Neoplasm ◽

Multiple Tumor

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Crosstalk between Prostate Cancer Cells and Tumor-Associated Fibroblasts Enhances the Malignancy by Inhibiting the Tumor Suppressor PLZF

Cancers ◽

10.3390/cancers12051083 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1083

Author(s):

Kum Hee Noh ◽

Ae Jin Jeong ◽

Haeri Lee ◽

Song-Hee Lee ◽

Eunhee Yi ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Suppressor ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Metastasis ◽

Tyrosine Phosphatase ◽

Migration And Invasion ◽

Metastatic Progression ◽

Prostate Cancer Cells ◽

Prostate Cancer Metastasis

Although prostate cancer is clinically manageable during the early stages of progression, metastatic progression severely compromises the prognosis and leads to mortality. Constitutive activation of STAT3 has been connected to prostate cancer malignancy, and abolishing the STAT3 activity may diminish tumor growth and metastasis. However, its suppressor genes and pathways have not been well established. In this study, we show that promyelocytic leukemia zinc finger (PLZF) has a putative tumor-suppressor function in prostate cancer by inhibiting phosphorylation of STAT3. Compared with a benign prostate, high-grade prostate cancer patient tissue was negatively correlated with PLZF expression. PLZF depletion accelerated proliferation and survival, migration, and invasion in human prostate cancer cells. Mechanistically, we demonstrated a novel role of PLZF as the transcriptional regulator of the tyrosine phosphatase SHP-1 that inhibits the oncogenic JAKs–STAT3 pathway. These results suggest that the collapse of PLZF expression by the CCL3 derived from fibroblasts accelerates the cell migration and invasion properties of prostate cancer cells. Our results suggest that increasing PLZF could be an attractive strategy for suppressing prostate cancer metastasis as well as for tumor growth.

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Inhibition of the histone demethylase, KDM5B, directly induces re-expression of tumor suppressor protein HEXIM1 in cancer cells

Breast Cancer Research ◽

10.1186/s13058-019-1228-7 ◽

2019 ◽

Vol 21 (1) ◽

Cited By ~ 5

Author(s):

Monica M. Montano ◽

I-Ju Yeh ◽

Yinghua Chen ◽

Chris Hernandez ◽

Janna G. Kiselar ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Cancer Cells ◽

Cancer Metastasis ◽

Critical Role ◽

Cell Phenotype ◽

Relative Role ◽

Western Blots ◽

Inhibition Of Proliferation ◽

Proliferation Assays

Abstract Background The tumor suppressor actions of hexamethylene bis-acetamide (HMBA)-inducible protein 1 (HEXIM1) in the breast, prostate, melanomas, and AML have been reported by our group and others. Increased HEXIM1 expression caused differentiation and inhibited proliferation and metastasis of cancer cells. Historically, HEXIM1 has been experimentally induced with the hybrid polar compound HMBA, but HMBA is a poor clinical candidate due to lack of a known target, poor pharmacological properties, and unfavorable ADMETox characteristics. Thus, HEXIM1 induction is an intriguing therapeutic approach to cancer treatment, but requires better chemical tools than HMBA. Methods We identified and verified KDM5B as a target of HEXIM1 inducers using a chemical proteomics approach, biotin–NeutrAvidin pull-down assays, surface plasmon resonance, and molecular docking. The regulation of HEXIM1 by KDM5B and KDM5B inhibitors was assessed using chromatin immunoprecipitation assays, RT-PCR, western blotting, and depletion of KDM5B with shRNAs. The regulation of breast cancer cell phenotype by KDM5B inhibitors was assessed using western blots, differentiation assays, proliferation assays, and a mouse model of breast cancer metastasis. The relative role of HEXIM1 in the action of KDM5B inhibitors was determined by depleting HEXIM1 using shRNAs followed by western blots, differentiation assays, and proliferation assays. Results We have identified a highly druggable target, KDM5B, which is inhibited by small molecule inducers of HEXIM1. RNAi knockdown of KDM5B induced HEXIM1 expression, thus validating the specific negative regulation of tumor suppressor HEXIM1 by the H3K4me3/2 demethylase KDM5B. Known inhibitors of KDM5B were also able to induce HEXIM1 expression, inhibit cell proliferation, induce differentiation, potentiate sensitivity to cancer chemotherapy, and inhibit breast tumor metastasis. Conclusion HMBA and 4a1 induce HEXIM1 expression by inhibiting KDM5B. Upregulation of HEXIM1 expression levels plays a critical role in the inhibition of proliferation of breast cancer cells using KDM5B inhibitors. Based on the novel molecular scaffolds that we identified which more potently induced HEXIM1 expression and data in support that KDM5B is a target of these compounds, we have opened up new lead discovery and optimization directions.

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Disruption of the Multiple Tumor Suppressor Gene MTS1/p16INK4a/CDKN2 by Illegitimate V(D)J Recombinase Activity in T-Cell Acute Lymphoblastic Leukemias

Blood ◽

10.1182/blood.v90.9.3720 ◽

1997 ◽

Vol 90 (9) ◽

pp. 3720-3726 ◽

Cited By ~ 50

Author(s):

Jean-Michel Cayuela ◽

Betty Gardie ◽

François Sigaux

Keyword(s):

T Cell ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Suppressor Gene ◽

Genetic Event ◽

Ca Repeat ◽

Multiple Tumor ◽

Human T Cell ◽

Exon 1 ◽

Cell Cycle Inhibitors

Abstract We have recently shown that the multiple tumor suppressor gene 1 (MTS1 ) encoding the p16INK4a and p19ARF cell-cycle inhibitors is inactivated by deletion or disruption in most human T-cell acute lymphoblastic leukemias (T-ALLs), representing the most frequent genetic event thus far described in this disease. To analyze the mechanism of these chromosomal events, we used cloning, sequencing, and/or polymerase chain reaction mapping to study 15 rearrangements occurring in the MTS1 locus. We found that these breakpoints occur in two clusters (MTS1bcrα and MTS1bcrβ ). The three rearrangements occurring in MTS1bcrα correspond to a recurrent recombination juxtaposing 5′ MTS2 exon 1 and 5′ MTS1 exon 1α sequences. Breakpoints for 10 of 12 rearrangements within MTS1bcrβ are located at a polymorphic (CA) repeat, suggesting that this sequence might play a role in the clustering. For both MTS1bcrα and MTS1bcrβ, sequence analyses and PCR mapping experiments show that the tightly clustered breakpoints are located in the vicinity of heptamers whose sequence is similar to those involved in the V(D)J recombination. Moreover, short deletions, GC-rich random nucleotide additions, and clone-specific junctional sequences are present in all cases, further suggesting that the rearrangements are due to illegitimate V(D)J recombinase activity. These data are the first demonstration that a tumor suppressor gene can be inactivated by the V(D)J recombinational mechanism. Moreover, they reinforce the view that this process, normally required for T-cell differentiation, plays a crucial role in the pathogenesis of T-ALL.

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