TISIDB

Summary
Symbol	FHIT
Name	fragile histidine triad
Aliases	fragile histidine triad gene; diadenosine 5',5'''-P1,P3-triphosphate hydrolase; dinucleosidetriphosphatase; ......
Chromosomal Location	3p14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cytoplasm. Mitochondrion. Nucleus.
Domain	PF01230 HIT domain
Function	Cleaves P(1)-P(3)-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP. Can also hydrolyze P(1)-P(4)-bis(5'-adenosyl) tetraphosphate (Ap4A), but has extremely low activity with ATP. Modulates transcriptional activation by CTNNB1 and thereby contributes to regulate the expression of genes essential for cell proliferation and survival, such as CCND1 and BIRC5. Plays a role in the induction of apoptosis via SRC and AKT1 signaling pathways. Inhibits MDM2-mediated proteasomal degradation of p53/TP53 and thereby plays a role in p53/TP53-mediated apoptosis. Induction of apoptosis depends on the ability of FHIT to bind P(1)-P(3)-bis(5'-adenosyl) triphosphate or related compounds, but does not require its catalytic activity, it may in part come from the mitochondrial form, which sensitizes the low-affinity Ca(2+) transporters, enhancing mitochondrial calcium uptake. Functions as tumor suppressor.

> Gene Ontology [ TOP ]
Biological Process	GO:0009894 regulation of catabolic process GO:0009895 negative regulation of catabolic process GO:0010498 proteasomal protein catabolic process GO:0031329 regulation of cellular catabolic process GO:0031330 negative regulation of cellular catabolic process GO:0032434 regulation of proteasomal ubiquitin-dependent protein catabolic process GO:0032435 negative regulation of proteasomal ubiquitin-dependent protein catabolic process GO:0042176 regulation of protein catabolic process GO:0042177 negative regulation of protein catabolic process GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process GO:0045861 negative regulation of proteolysis GO:0061136 regulation of proteasomal protein catabolic process GO:0072331 signal transduction by p53 class mediator GO:0072332 intrinsic apoptotic signaling pathway by p53 class mediator GO:0097193 intrinsic apoptotic signaling pathway GO:1901799 negative regulation of proteasomal protein catabolic process GO:1903050 regulation of proteolysis involved in cellular protein catabolic process GO:1903051 negative regulation of proteolysis involved in cellular protein catabolic process GO:1903362 regulation of cellular protein catabolic process GO:1903363 negative regulation of cellular protein catabolic process
Molecular Function	GO:0004551 nucleotide diphosphatase activity GO:0031625 ubiquitin protein ligase binding GO:0044389 ubiquitin-like protein ligase binding GO:0047710 bis(5'-adenosyl)-triphosphatase activity
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa00230 Purine metabolism
Reactome	-

Summary
Symbol	FHIT
Name	fragile histidine triad
Aliases	fragile histidine triad gene; diadenosine 5',5'''-P1,P3-triphosphate hydrolase; dinucleosidetriphosphatase; ......
Chromosomal Location	3p14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between FHIT and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between FHIT and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
22451343	Fibrosarcoma	Promote immunity	In contrast, silencing of the Fhit gene produced the transcriptional down-regulation of APM components and MHC-I heavy chains and decreased MHC-I surface expression. These data indicate that defects in Fhit expression may promote MHC-I down-regulation in cancer cells and allow escape from immunosurveillance(#).

Summary
Symbol	FHIT
Name	fragile histidine triad
Aliases	fragile histidine triad gene; diadenosine 5',5'''-P1,P3-triphosphate hydrolase; dinucleosidetriphosphatase; ......
Chromosomal Location	3p14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of FHIT in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	FHIT
Name	fragile histidine triad
Aliases	fragile histidine triad gene; diadenosine 5',5'''-P1,P3-triphosphate hydrolase; dinucleosidetriphosphatase; ......
Chromosomal Location	3p14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of FHIT in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0.25	0.64
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.392	0.808
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.716	0.577
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.029	0.951
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.299	0.764
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.304	0.774
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.522	0.0917
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.329	0.704
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.762	0.431
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	-1.066	0.331
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	-0.89	0.561
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.028	0.844

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of FHIT in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	1.4	2.3	0.469
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	1.7	2	0.532
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	0	0	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	0	0	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	FHIT
Name	fragile histidine triad
Aliases	fragile histidine triad gene; diadenosine 5',5'''-P1,P3-triphosphate hydrolase; dinucleosidetriphosphatase; ......
Chromosomal Location	3p14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of FHIT. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	FHIT
Name	fragile histidine triad
Aliases	fragile histidine triad gene; diadenosine 5',5'''-P1,P3-triphosphate hydrolase; dinucleosidetriphosphatase; ......
Chromosomal Location	3p14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of FHIT. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by FHIT. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	FHIT
Name	fragile histidine triad
Aliases	fragile histidine triad gene; diadenosine 5',5'''-P1,P3-triphosphate hydrolase; dinucleosidetriphosphatase; ......
Chromosomal Location	3p14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of FHIT. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	FHIT
Name	fragile histidine triad
Aliases	fragile histidine triad gene; diadenosine 5',5'''-P1,P3-triphosphate hydrolase; dinucleosidetriphosphatase; ......
Chromosomal Location	3p14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of FHIT expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	FHIT
Name	fragile histidine triad
Aliases	fragile histidine triad gene; diadenosine 5',5'''-P1,P3-triphosphate hydrolase; dinucleosidetriphosphatase; ......
Chromosomal Location	3p14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between FHIT and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	FHIT
Name	fragile histidine triad
Aliases	fragile histidine triad gene; diadenosine 5',5'''-P1,P3-triphosphate hydrolase; dinucleosidetriphosphatase; ......
Chromosomal Location	3p14.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting FHIT collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting FHIT.

ID	Name	Drug Type	Targets	#Targets
DB02373	Adenosine Monotungstate	Small Molecule	FHIT	1
DB04173	Fructose	Small Molecule	FHIT	1
DB04389	Ado-P-Ch2-P-Ps-Ado	Small Molecule	FHIT	1

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