MINDY4 Data Analysis

HGNC Gene Name
MINDY lysine 48 deubiquitinase 4
HGNC Gene Symbol
MINDY4
Identifiers
hgnc:21916 NCBIGene:84182 uniprot:Q4G0A6
Orthologs
mgi:3583959 rgd:1562590
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for MINDY4
Number of Papers
1 retrieved on 2022-05-22

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with MINDY4using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier GO Name GO Type p-value p-value (adj.) q-value

Literature Mining

INDRA was used to automatically assemble known mechanisms related to MINDY4 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
MINDY4 affects EGFR
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MINDY4 increases the amount of EGFR.
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MINDY4 increases the amount of EGFR. 5 / 5
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Intriguingly, si-FAM188B treatment increased EGFR mRNA levels but decreased its protein levels, which was reversed by treatment with the proteasomal inhibitor MG132, indicating that FAM188B regulates EGFR levels via the proteasomal pathway.

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More interestingly, FAM188B re-expression could recover EGFR receptor levels that had been decreased by FAM188B knockdown.

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All these data suggest that FAM188B knockdown downregulates EGFR levels through the proteasome degradation pathway and inactivates multiple pathways involved in cell proliferation and survival.

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In this regard, it is very intriguing that FAM188B knockdown decreased levels of total EGFR and p-EGFR in both attached and detached cells (XREF_FIG A, D).

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Interestingly, FAM188B knockdown downregulated EGFR protein levels in both attached and suspended cells regardless of EGFR mutation (XREF_FIG A).
MINDY4 activates EGFR.
| 3
MINDY4 activates EGFR. 3 / 3
| 3

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However, FAM188B knockdown decreased EGFR protein levels (XREF_FIG A).

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FAM188B knockdown decreased the activities of several oncogenic proteins downstream of EGFR that are involved in anoikis resistance, including pAkt, pSrc, and pSTAT3, with little changes to their protein levels.

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It is possible that EGFR downregulation induced by si-FAM188B results in inactivation of those signaling pathways, which are involved not only in the determination of anoikis resistance but also metastatic characteristics, including migration and invasion [XREF_BIBR].
MINDY4 decreases the amount of EGFR.
| 2
MINDY4 decreases the amount of EGFR. 2 / 2
| 2

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Interestingly, FAM188B knockdown did not decrease but rather increased EGFR mRNA levels (XREF_FIG B).

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Contrary to expectation, FAM188B knockdown upregulated EGFR mRNA levels (XREF_FIG B).
MINDY4 inhibits EGFR.
| 1
MINDY4 inhibits EGFR. 1 / 1
| 1

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FAM188B knockdown induced EGFR downregulation and inactivation of survival related signaling molecules, indicating that FAM188B could be a potential target to control tumor metastasis.
| 3 4
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FAM188B knockdown induced cell growth inhibition due to an increase in apoptosis in colon cancer cell lines.

eidos
FAM188B knockdown induced the inhibition of cell growth along with the downregulation of mRNA and protein levels of FOXM1 .

eidos
FAM188B was downregulated by si-RNA targeting FAM188B ( Figure 1B ) , and cell growth was significantly inhibited by FAM188B knockdown as assessed by 3 - ( 4,5 - dimethylthiazol-2-yl ) -5 - ( 3-carboxyme-thoxyphenyl ) -2 - ( 4-sulfophenyl ) -2 H-tetrazolium ( MTS ) assay in A549 , H1299 , and H1975 cells ( Figure 1C ) .

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FAM188B knockdown induced the inhibition of cell growth along with the downregulation of mRNA and protein levels of FOXM1.

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FAM188B was downregulated by si-RNA targeting FAM188B (XREF_FIG B), and cell growth was significantly inhibited by FAM188B knockdown as assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxyme-thoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay in A549, H1299, and H1975 cells (XREF_FIG C).

eidos
In addition , FAM188B knockdown decreased cell growth in the 3D culture condition , which mimics in vivo conditions ( Figure 4E ) .

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In addition, FAM188B knockdown decreased cell growth in the 3D culture condition, which mimics in vivo conditions (XREF_FIG E).
| 3 3

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Here, we demonstrate that FAM188B knockdown sensitizes human lung cancer cell lines to anoikis upon cell detachment and inhibits lung metastasis in vivo.

eidos
FAM188B knockdown inhibits various metastatic characteristics and tumor metastasis .

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FAM188B knockdown inhibits various metastatic characteristics and tumor metastasis.

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Here, we demonstrate that FAM188B knockdown makes lung cancer cells sensitive to anoikis and inhibits lung metastasis.

eidos
FAM188B Downregulation Sensitizes Lung Cancer Cells to Anoikis via EGFR Downregulation and Inhibits Tumor Metastasis In Vivo Simple Summary Cancer cells should acquire anoikis resistance for successful metastasis .

eidos
FAM188B Downregulation Sensitizes Lung Cancer Cells to Anoikis via EGFR Downregulation and Inhibits Tumor Metastasis In Vivo .
MINDY4 affects TP53
| 6
MINDY4 inhibits TP53.
| 3
MINDY4 inhibits TP53. 3 / 3
| 3

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Therefore, elevated expression of FAM188B in tumor tissues suggests that FAM188B would inhibit p53 activation and thereby provide tolerance against stressful conditions.

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FAM188B silencing activates p53 and its downstream pathway.

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FAM188B knockdown increased p53 as well as Ser15 phosphorylated p53, and thus enhanced protein levels of p53 regulated genes, including p21, PUMA, and BAX, which are in the apoptosis pathway.
MINDY4 decreases the amount of TP53.
| 2
MINDY4 decreases the amount of TP53. 2 / 2
| 2

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To determine how FAM188B knockdown enhances p53 protein levels, we identified FAM188B interacting proteins revealed by LC/MS-MS.

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However, double silencing of USP7 and FAM188B restored the p53 level.
MINDY4 activates TP53.
| 1
MINDY4 activates TP53. 1 / 1
| 1

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These results suggest that FAM188B downregulation activates p53, and thus upregulates apoptosis related genes, including BAX, and PUMA, and leads to cell death.
| 2 3
| 2 2

eidos
We also observed that FAM188B knockdown induced apoptosis in the suspension culture as determined by flow cytometry analysis of annexin V / PI stained cells ( Figure 2D ) .

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There were increases in annexin V/PI stained cells by si-FAM188B-treatment, indicating that FAM188B knockdown induces apoptosis (XREF_FIG D and Figure S1A).

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We also observed that FAM188B knockdown induced apoptosis in the suspension culture as determined by flow cytometry analysis of annexin V/PI stained cells (XREF_FIG D).

eidos
There were increases in annexin V / PI-stained cells by si-FAM188B-treatment , indicating that FAM188B knockdown induces apoptosis ( Figure 1D and Figure S1A ) .
| 1

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These results suggest that FAM188B downregulation activates p53, and thus upregulates apoptosis related genes, including BAX, and PUMA, and leads to cell death.

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FAM188B knockdown significantly decreased both invasion (XREF_FIG A) and migration (XREF_FIG B) in three cell lines.

eidos
FAM188B knockdown significantly decreased both invasion ( Figure 4A ) and migration ( Figure 4B ) in three cell lines .

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FAM188B knockdown attenuated invasion, migration, adhesion, and wound closure (XREF_FIG A-D).

eidos
FAM188B knockdown attenuated invasion , migration , adhesion , and wound closure ( Figure 4A-D ) .
| 1 2
| 1 2

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FAM188B knockdown attenuated invasion, migration, adhesion, and wound closure (XREF_FIG A-D).

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In addition, cell adhesion was also retarded in cells treated with si-FAM188B (XREF_FIG C).

eidos
FAM188B knockdown attenuated invasion , migration , adhesion , and wound closure ( Figure 4A-D ) .
MINDY4 affects FOXM1
| 2 1
MINDY4 activates FOXM1. 3 / 3
| 2 1

eidos
Recently , we reported that FAM188B knockdown decreased levels of FOXM1 , an oncogenic transcription factor , with an increase in its ubiquitination in A549 cells [ 14 ] .

eidos
More interestingly , FAM188B knockdown decreased FOXM1 , an oncogenic transcription factor [ 23 ] , in both attached and suspended conditions ( Figure 3D ) .

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More interestingly, FAM188B knockdown decreased FOXM1, an oncogenic transcription factor [XREF_BIBR], in both attached and suspended conditions (XREF_FIG D).
MINDY4 affects BIRC5
| 2 1
MINDY4 activates BIRC5.
| 2
MINDY4 activates BIRC5. 2 / 2
| 2

eidos
FAM188B knockdown decreased levels of Survivin , which is an anti-apoptotic protein that plays a critical role in anoikis resistance [ 14 ] .

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FAM188B knockdown also resulted in downregulation of Survivin and cell cycle-related proteins , which are direct targets of FOXM1 .
MINDY4 increases the amount of BIRC5.
| 1
MINDY4 increases the amount of BIRC5. 1 / 1
| 1

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FAM188B knockdown decreased levels of Survivin, which is an anti-apoptotic protein that plays a critical role in anoikis resistance [XREF_BIBR].
MINDY4 affects cell death
| 2
| 2

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FAM188B downregulation leads to cell death in vitro.

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These results suggest that FAM188B downregulation activates p53, and thus upregulates apoptosis related genes, including BAX, and PUMA, and leads to cell death.
MINDY4 affects STAT3
| 2
MINDY4 activates STAT3. 2 / 2
| 2

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Intriguingly, FAM188B knockdown inactivated Src, Akt, and STAT3, not only in suspension but also in attached cells (XREF_FIG D).

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STAT3 activation was dramatically reduced by FAM188B knockdown (XREF_FIG D), and consistently phospho-STAT3 immunostaining decreased in the FAM188B-knockdown lung tumor tissue.
| 2

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FAM188B enhances cell survival via interaction with USP7.

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FAM188B knockdown decreased cell viability in lung cancer cells.
2 |
Bisphenol A increases the amount of MINDY4.
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Bisphenol A increases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
Bisphenol A decreases the amount of MINDY4.
1 |
Bisphenol A decreases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available

ctd
No evidence text available
1 |
Thioacetamide increases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
Tetrachloromethane increases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
Sunitinib affects MINDY4
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Sunitinib decreases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
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Sodium arsenite decreases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
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Silicon dioxide increases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
1 |
Hsa-miR-484 decreases the amount of MINDY4. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
| 1
| 1

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Doxycycline induced FAM188B short hairpin RNA (shRNA), which led to FAM188B downregulation.
Dichloroacetic acid increases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
Cytarabine affects MINDY4
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Cytarabine decreases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
All-trans-retinoic acid decreases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
Acrylamide affects MINDY4
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Acrylamide decreases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
TP53 affects MINDY4
1 |
TP53 decreases the amount of MINDY4. 1 / 1
1 |

biopax:msigdb
No evidence text available

eidos
More interestingly , FAM188B re-expression could recover EGFR receptor levels that had been decreased by FAM188B knockdown ( Figure S3A ) .
| 1

eidos
Contrary to expectation , FAM188B knockdown upregulated EGFR mRNA levels ( Figure 3B ) .
MINDY4 affects annexin
| 1
| 1

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In addition, FAM188B knockdown increased the population of annexin V/PI stained cells.

eidos
FAM188B knockdown induced increased caspase 3 activation , as assessed by its cleavage , and thus increased PARP cleavage ( Figure S1B ) , indicating activation of apoptosis signaling by FAM188B knockdown .
MINDY4 affects SRC
| 1
MINDY4 activates SRC. 1 / 1
| 1

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Intriguingly, FAM188B knockdown inactivated Src, Akt, and STAT3, not only in suspension but also in attached cells (XREF_FIG D).
MINDY4 affects AKT
| 1
MINDY4 activates AKT. 1 / 1
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Intriguingly, FAM188B knockdown inactivated Src, Akt, and STAT3, not only in suspension but also in attached cells (XREF_FIG D).
MINDY4 affects 3D
| 1
MINDY4 inhibits 3D. 1 / 1
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Moreover, FAM188B downregulation reduced metastatic characteristics, such as cell adhesion, invasion, and migration, as well as growth in 3D culture conditions.
MAZ affects MINDY4
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MAZ decreases the amount of MINDY4. 1 / 1
1 |

biopax:msigdb
No evidence text available
GW 4064 affects MINDY4
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GW 4064 increases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
Cuprizone affects MINDY4
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Cuprizone increases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
Antirheumatic Agents increases the amount of MINDY4. 1 / 1
1 |

ctd
No evidence text available
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ctd
No evidence text available
17alpha-ethynylestradiol decreases the amount of MINDY4. 1 / 1
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ctd
No evidence text available
1 |

ctd
No evidence text available