Comprehensive analysis of the role of ubiquitin-specific peptidases in colorectal cancer: A systematic review

Table 1 The queries used to systematically search the databases

Database	Search strategy
MEDLINE, 124	(((Colorectal Cancer, Hereditary Nonpolyposis, Type 8, Colorectal Cancer, Hereditary Nonpolyposis, Type 6, Colorectal Cancer, Hereditary Nonpolyposis, Type 7, Colorectal Cancer, Hereditary Nonpolyposis, Type 3, Colorectal Cancer, Hereditary Nonpolyposis, Type 4, Colorectal Cancer, Hereditary Nonpolyposis, Type 5) OR (("Colorectal Neoplasms"[Mesh] OR "Colorectal Neoplasms, Hereditary Nonpolyposis"[Mesh] OR "Colitis-Associated Neoplasms"[Mesh])) OR ((Colorectal Cancer[Title/Abstract])) OR (Colorectal Neoplasms[Title/Abstract]))) AND ((((((((((((((Ubiquitin Specific Proteases[Title/Abstract]) OR (Ubiquitin-Specific Peptidase[Title/Abstract])) OR (Peptidase, Ubiquitin-Specific[Title/Abstract])) OR (Ubiquitin Specific Peptidase[Title/Abstract])) OR (Ubiquitin-Specific Peptidases[Title/Abstract])) OR (Peptidases, Ubiquitin-Specific[Title/Abstract])) OR (Ubiquitin Specific Peptidases[Title/Abstract])) OR (Ubiquitin-Specific Protease[Title/Abstract])) OR (Protease, Ubiquitin-Specific[Title/Abstract])) OR (Ubiquitin Specific Protease[Title/Abstract])) OR (Ubiquitin-Specific Protease Family[Title/Abstract])) OR (Protease Family, Ubiquitin-Specific[Title/Abstract])) OR (Ubiquitin Specific Protease Family[Title/Abstract])) OR ((Ubiquitin-Specific Peptidase[MeSH Terms]) OR (Ubiquitin Specific Proteases[MeSH Terms])))
Scopus, 139	(TITLE-ABS-KEY ((((colorectal AND neoplasms) OR (colorectal AND neoplasms, AND hereditary AND nonpolyposis) OR (colitis-associated AND neoplasms) OR (colorectal AND cancer, AND hereditary AND nonpolyposis, AND type 8) OR (colorectal AND cancer, AND hereditary AND nonpolyposis, AND type 6) OR (colorectal AND cancer, AND hereditary AND nonpolyposis, AND type 7) OR (colorectal AND cancer, AND hereditary AND nonpolyposis, AND type 3) OR (colorectal AND cancer, AND hereditary AND nonpolyposis, AND type 4) OR (colorectal AND cancer, AND hereditary AND nonpolyposis, AND type 5) OR (colorectal AND cancer) ) ) ) ) AND ((TITLE-ABS-KEY (ubiquitin AND specific AND proteases) OR TITLE-ABS-KEY (ubiquitin-specific AND peptidase) OR TITLE-ABS-KEY (peptidase, AND ubiquitin-specific) OR TITLE-ABS-KEY (ubiquitin AND specific AND peptidase) OR TITLE-ABS-KEY (ubiquitin-specific AND peptidases) OR TITLE-ABS-KEY (peptidases, AND ubiquitin-specific) OR TITLE-ABS-KEY (ubiquitin AND specific AND peptidases) OR TITLE-ABS-KEY (ubiquitin-specific AND protease) OR TITLE-ABS-KEY (protease, AND ubiquitin-specific) OR TITLE-ABS-KEY (ubiquitin AND specific AND protease) OR TITLE-ABS-KEY (ubiquitin-specific AND protease AND family) OR TITLE-ABS-KEY (protease AND family, AND ubiquitin-specific) OR TITLE-ABS-KEY (ubiquitin AND specific AND protease AND family) ) ) AND PUBYEAR > 2007 AND PUBYEAR < 2024
Web of Science, 473	(((((((((TS=(Colorectal Neoplasms)) OR TS=(Colorectal Neoplasms, Hereditary Nonpolyposis)) OR TS=(Colitis-Associated Neoplasms)) OR TS=(Colorectal Cancer, Hereditary Nonpolyposis, Type 8)) OR TS=(Colorectal Cancer, Hereditary Nonpolyposis, Type 6)) OR TS=(Colorectal Cancer, Hereditary Nonpolyposis, Type 7)) OR TS=(Colorectal Cancer, Hereditary Nonpolyposis, Type 3)) OR TS=(Colorectal Cancer, Hereditary Nonpolyposis, Type 4)) OR TS=(Colorectal Cancer, Hereditary Nonpolyposis, Type 5)) OR TS=(Colorectal Cancer) AND ((((((((((((TS=(Ubiquitin Specific Proteases)) OR TS=(Ubiquitin-Specific Peptidase)) OR TS=(Peptidase, Ubiquitin-Specific)) OR TS=(Ubiquitin Specific Peptidase)) OR TS=(Ubiquitin-Specific Peptidases)) OR TS=(Peptidases, Ubiquitin-Specific)) OR TS=(Ubiquitin Specific Peptidases)) OR TS=(Ubiquitin-Specific Protease)) OR TS=(Protease, Ubiquitin-Specific)) OR TS=(Ubiquitin Specific Protease)) OR TS=(Ubiquitin-Specific Protease Family)) OR TS=(Protease Family, Ubiquitin-Specific)) OR TS=(Ubiquitin Specific Protease Family)

Table 2 A summary of the data extracted from the 135 articles included in the systematic review

No.	Gene symbol	Role in tumors	Cellular localizatioa	Target(s)	Functions and pathways	Inhibitor(s)	Ref.
1	USP1	Oncogene	Nucleus	Cyclin A/D/E, Bcl2, MCL1, FANCD1, ID1	Cell cycle, DNA Repair, apoptosis	ML323	Xu et al[24]
2	USP2	Oncogene	Cytoplasm, cytoplasm (perinuclear region), isoform 4: nucleus, membrane, cytoplasm	Cyclin D1, PER1, CRY1, HDM2/p53, FASN, LDLR, TRAF6, TBK1, TGFBR1-TGFBR2 complex	Cell survival, circadian rhythm, cell metabolism, inflammatory response, antiviral response, metastasis, cell growth, cell cycle (G0-G1), HR-mediated DNA repair	ML364	Davis et al[26] and Luo et al[76]
	USP2a	Oncogene		Cyclin D1	Cell cycle progression, development	LCAHA	Magiera et al[23]
4	USP3	Tumor suppressor	Nucleus	SMAD4	TGF-β pathway, CRC migration, metastasis, invasion	miR-224	Das et al[33], Wang et al[71], and Zheng et al[87]
		Oncogene		Androgen receptor, RASGRP3, Cdc25A	MAPK pathway, apoptosis, cell cycle progression, CRC non-invasive biomarker	AC092894.1
5	USP4	Oncogene	Cytoplasm, nucleus	PRL-3, β-catenin, Rheb	AKT, EMT, E-Cadherin, Wnt/β-catenin pathway, colony formation, mTORC1 activation, tumorigenesis, progression	Vialinin A, PR619, NR (neutral red)	Yun et al[56], Xing et al[65], Nguyen et al[90], Deng et al[97], Wang et al[98], and Zhao et al[99]
6	USP5	Tumor suppressor	Cytosol, lysosome, nucleus	ORP8	ER stress, apoptosis, progression/drug resistance	G9, vialinin A, WP1130, EOAI3402143, AM146, RA-9, RA-14, PR619, doxorubicin	Xu et al[81], Zhang et al[100], and Ning et al[101]
		Oncogene		TUFM	Cell growth
7	USP6	Oncogene	Cell membrane, cytoplasm, endosome		Deubiquitination, development, progression		Zeng et al[72]
8	USP6NL	Oncogene	Golgi apparatus, cytoplasmic vesicle	β-catenin (P27, c-MYC, CyclinD1)	Wnt/β-catenin pathway, proliferation, metastasis, progression		Sun et al[64]
9	USP7 (HAUSP)	Tumor suppressor	Nucleus, cytoplasm, nucleus (PML body), chromosome	MDM2, p53	Tumor growth, development, progression, drug resistance	IL-6/STAT3/HDAC-1, P22077, HBX41, P0045204, P005091, N-benzylpiperidinol, HBX19,FT671, GNE6640, GNE6776, C7, C19, parthenolide	Choi et al[36], Novellasdemunt et al[58], Novellasdemunt et al[59], Sarkar[60], Basu et al[61], Hou et al[62], Zhou et al[80], An et al[91], Weinstock et al[92], Li et al[93], Nicholson et al[102], Colland et al[103], Qian et al[104], Bufalieri et al[105], Li et al[106], Becker et al[107], Yang et al[108], Du et al[109], Zhu et al[110]
		Oncogene		DNMT1, β-catenin, FAM188B, DDX3X, c-MYC, P53, HDM2, DNA damage repair proteins DNA polymerase eta (Polη), PCNA	Tumor growth, WNT/β-catenin pathway, apoptosis, cell growth, stress-tolerance pathway, tumorigenesis, proliferation
10	USP9X	Tumor suppressor	Cytosol, cell projection (growth cone), cytoplasm (cytoskeleton, cilium axoneme)	FBW7	C-MYC, C-JUN, cyclin E, development, progression, drug resistance (5-FU)	G9, WP1130, PR619	Harris et al[27], Peddaboina et al[40], and Tian et al[111]
		Oncogene		BCL-XL, MCL-1	Apoptosis
11	USP10	Tumor suppressor	Cytoplasm, nucleus, early endosome	SIRT6, P53	c-MYC, progression	P22077, HBX19818, spautin-1, PR619	Lin et al[28], Kim et al[29], Li et al[34], Reissland et al[51], Li et al[78], Ouyang et al[112], and Ye et al[113]
		Oncogene		NLRP7, MSI2, miR-1286, β-catenin	Tumor promotion, NF-kB pathway, cancer proliferation, invasion, metastasis, WNT/β-catenin pathway
12	USP11	Tumor suppressor	Nucleus, cytoplasm, chromosome	P21	Apoptosis	miR-132-3P	Zhang et al[42], Sun et al[66], Liao et al[67], Tian et al[111], Lee et al[114], Huang et al[115], and Sun et al[116]
		Oncogene		PPP1CA, IGF2BP3, Cyclin D1, c-IAP2, VCP	Tumor growth, metastasis, apoptosis, ERK/MAPK pathway, autophagy AMPK/Akt/mTOR pathway, proliferation, migration, development, progression, drug resistance (5-FU)
13	USP13	Tumor suppressor	Cytosol, nucleoplasm, nucleus	PTEN	Cell proliferation, glycolysis, development	miR-135b	Xiang et al[117]
14	USP14	Oncogene	Cytoplasm, cell membrane	JNK, β-catenin, Dvl, NLRC5, RIG-I, FASN, CXCR4	MAPK/JNK signaling, immune regulation, tumorigenesis, proliferation, Wnt/β-catenin pathway, liver/lymph node metastases, progression, drug resistance (IDO1), correlated with pathological stage	b-AP15	Sarkar[60], Liu et al[118], Mofers et al[119], Du et al[120], and Shi et al[121]
15	USP15	Tumor suppressor	Cytoplasm, nucleus, mitochondrion	APC	Wnt/β-catenin pathway, development		Huang et al[122]
16	USP17	Tumor suppressor	Nucleus, endoplasmic reticulum		DNA damage response, chemosensitization	ZEB1	Wang et al[123]
17	USP18	Oncogene	Cytoplasm, nucleus	SNAIL	EMT, development, progression, drug resistance		Huang et al[68], and Zhang et al[124]
18	USP19	Oncogene	Endoplasmic reticulum membrane	ME1	Lipogenesis, NADPH production, inhibiting ROS, tumorigenesis, carcinogenesis, development		Zhu et al[125]
19	USP20	Oncogene	Cytoplasm, endoplasmic reticulum, cytoplasm (perinuclear region), cytoplasm (centrosome)	SOX4, ADORA2A, CD160, CD27, TNFRSF25, MRP1, MRP3, MRP5	E-Cadherin, N-Cadherin, SNAIL, Slug, migration, Invasion, Metastasis, Notch/Hedgehog/β-catenin pathway, progression, drug Resistance	PR619	Guan et al[53], Jin et al[79], and Ming et al[86]
20	USP21	Oncogene	Cytoplasm, nucleus	Fra-1, RIG-I, NANOG, Foxp3	Metastasis, apoptosis, DNA repair, MMP1, tumor development/growth, NF-κB pathways, progression	Gallic Acid, BAY-805	Kang et al[52], Yun et al[73], Deng et al[94], and Göricke et al[95]
21	USP22	Tumor suppressor	Nucleus	SIRT1, SPARC(H2B)	STAT3-MMP9 pathway, mTOR, inflammation-associated CRC	PR619, miR-30a-5p	Lin et al[25], Jiang et al[48], Yan et al[49], Miao et al[50], Li et al[54], Guo et al[96], Liu et al[126], Jiang et al[127], Xu et al[128], Ao et al[129], Ao et al[130], Kosinsky et al[131], Liu et al[132], Sippl et al[133], Liu et al[134], Kapoor[135], Liu et al[136], Wang et al[137], Gennaro et al[138], Kosinsky et al[139], He et al[140], Feng et al[141], Kosinsky et al[142], Xian et al[143], and Kotelevets et al[144]
		Oncogene		AP-4, BMI-1, PD-L1, β-catenin, ZRANB1, Sox9, FOXP3, Akt, INK4a, ARF, CCND1, SNHG16, Axin2 miR-132-3p, MVP, cyclinD2 c-MYC, Pakt, CCND1(CyclinD1), H2B(RNF2), HSP90, AB1	Cell transition (G1-S)/(G2-M), EMT, Wnt/β-catenin pathway, RNF-22, proliferation, invasion, stemness, INK4a/ARF pathway, AKT signaling, apoptosis, immune escape, tumorigenesis, lymph node metastasis, development, progression, drug resistance (5-FU, Ganetespib), therapy resistant phenotype
22	USP25	Oncogene	Cytoplasm, nucleus	STAT3, SOCS3, EGFR	WNT pathway, EGF pathway, tumorigenesis, development	Vismodegib	Wang et al[30] and Wang et al[55]
23	USP28	Oncogene	Nucleus (nucleoplasm)	FBW7α, FOX1, NICD1, FOXC1, FBP1, Checkpoint	c-MYC, c-JUN, aerobic glycolysis, notch signaling, proliferation, tumorigenesis, progression	Vismodegib, FT206	Wang et al[30], Diefenbacher et al[31], Bernhard et al[32], Zhou et al[89], Popov et al[145], Liu et al[146], Xu et al[147], and Ren et al[148]
24	USP29	Oncogene	Cytoplasm (perinuclear region)	KIAA1429, SOX8	Proliferation, DNA damage, apoptosis, migration, invasion, progression		Chandrasekaran et al[149] and Li et al[150]
25	USP33	Tumor suppressor	Cytoplasm (perinuclear region), cytoplasm (centrosome), Golgi apparatus	ROBO1	SLIT2 pathway, progression		Huang et al[74]
26	USP34	Oncogene	Cytosol, nucleus	AXIN1, AXIN2	WNT pathway, development		Lui et al[151]
27	USP35	Oncogene	Cytosol, nucleus	FUCA1, NER	Proliferation, drug resistance (5-FU/OXA)		Xiao et al[85]
28	USP38	Tumor suppressor	Cytosol, nucleus	HDAC3, HMX3	Stemness markers, apoptosis, KRAS pathways, proliferation, migration, invasion, development, progression, drug resistance		Zhan et al[45], Wang et al[77], and Liu et al[82]
		Oncogene		LSD1	Proliferation, cell colony formation
29	USP39	Oncogene	Nucleus	β-catenin, TCF-4, MMP2, MMP9, KRAS, P21, CHK2, TCF/LEF, Aurora B	Wnt/β-catenin pathway, cell Cycle progression, c-MYC, cell Growth, cyclin D1, PPARd, invasion, tumorigenesis, proliferation, apoptosis, angiogenesis, spindle checkpoint and cytokinesis, colony formation, development		Yuan et al[41], Yuan et al[63], Fraile et al[152], Remitha et al[153]
30	USP42	Tumor suppressor	Cytosol, nucleoplasm, nucleus	RNF43, ZNRF3	WNT pathway		Giebel et al[57]
				Mesenchymal genes, Endothelial Genes	EMT, development, progression
31	USP43	Oncogene	Nucleoplasm	ZEB1	EMT pathway, proliferation, migration, invasion, progression		Ye et al[154]
32	USP44	Tumor suppressor	Chromatin, cytoplasm, mitotic spindle, nucleoplasm, nucleus	PCNA, cleaved-caspase3, Axin 1	Apoptosis, colorectal neoplasia, Wnt/β-catenin pathway, development, progression		Huang et al[38], Lou et al[39], and Sloane et al[155]
33	USP46	Tumor suppressor	Cytosol, nucleus	PHLPP	AKT pathway, development, progression hypoxia-induced drug resistance		Wen et al[83], and Li et al[156]
34	USP47	Oncogene	Cytoplasm	SNAIL, LINC00668, β-catenin, SATB1, SMURF2, YAP, RP52	EMT, stemness, tumor growth, chromatin remodeling, proliferation, migration, invasion, hippo Pathway, RP52-MDM2 interaction, colony formation, development, progression	Parthenolide, P5091, Cpd14, P22077, PR619	Cho et al[37], Zhang et al[46], Yu et al[47], Yan et al[75], Choi et al[157], Yu et al[158], Pan et al[159], and Pan et al[160]
35	USP49	Tumor suppressor	nucleus	miR-5000-3P	PI3K/AKT pathway, proliferation, migration, progression, drug sensitivity (oxaliplatin)		Tu et al[43], and Zhuang et al[84]
		Oncogene		BAG2	Apoptosis
36	USP54	Oncogene	Mitochondria		Proliferation, migration, invasion, tumorigenesis, development, progression		Fraile et al[161]

^aThe subcellular localization of all genes except for USP54 is based on the UniProt database; USP54 localization is based on the Human Protein Atlas.