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

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.