Table 2.

E3 ligases and DUBs affecting the oxygen-independent regulation of HIFs and their involvement in cancer.

Enzymes	Involvement in HIF Regulation	Involvement in Cancer	References
Ub E3 Ligases
RACK1	Competes with HSP90 for binding to HIF-1α to drive HIF-1α degradation	Overexpressed in nonsmall cell lung cancer, pulmonary adenocarcinoma, hepatocellular carcinoma, glioma, and breast cancer Reduced in gastric cancer	[87,166,167,168,169,170,171,172,173]
CHIP	Promotes HIF-1α but not HIF-2α degradation via both proteasomal or lysosomal machinery	Overexpressed in gallbladder carcinoma and esophageal and prostate cancer Reduced in breast, gastric, pancreatic, colorectal, and nonsmall cell lung cancer	[46,94,95,96,97,174,175,176,177,178,179,180,181]
MDM2	Regulates HIF-1α stability directly due to E3 ligase activity or indirectly by forming a ternary complex, which is degraded in a p53-dependent manner	Overexpressed in mesothelioma and in ovarian cancer	[98,99,182,183,184]
Fbw7	Recruited to GSK-3-phosphorylated HIF-1α for proteasomal degradation.	Highly mutated in cholangiocarcinomas and T-cell acute lymphocytic leukemia Reduced in glioma, pancreatic cancer Overexpression of FBW7 correlates with better survival of patients with colorectal cancer Regulates cell migration and angiogenesis in an HIF-1α-dependent manner	[110,111,112,185,186,187,188]
HAF	Selectively degrades HIF-1α and promotes HIF-2α transactivation during hypoxia	Associated with decreased progression-free survival in patients with clear-cell renal cell carcinoma Overexpression promotes GBM initiation and progression in mice Overexpressed in brain, breast, and colorectal cancer	[101,102,189,190,191]
TRAF6	Increases HIF-1α polylysine-63 ubiquitylation, protecting it from proteasomal degradation; TRAF6-ATM-H2AX signaling axis promotes HIF1α stabilization and activation	Predicts poor survival outcome in human breast, urothelial bladder, and gastric cancer patients Overexpressed in esophageal and pancreatic cancer and melanoma	[104,192,193,194,195,196]
Cullin 5-containing	Involved in HSP90-mediated regulation of HIF-1α stability	Reduced in breast and gastric cancer and in both endometrioid and serous endometrial adenocarcinomas Has antiproliferative effect in cervical and hepatocellular cancer	[88,197,198,199,200,201]
KLEIP-containing	By reducing levels of PML, leads to a activation of mTOR, which promotes HIF-1α signaling; stabilizes mRNA expression of HIF-2α	Promotes tumor angiogenesis and tumor growth that is overexpressed in human prostate cancer mice	[107,108]
BRCA1	Regulates stability of HIF-1α (NRM)	Highly mutated in breast and ovarian cancer	[109,202,203]
Pellino3	Ubiquitylates TRAF6 with polylysine-63 to block its interaction with HIF-1α, making it more prone to proteasomal degradation		[106]
DUBs
USP7	Deubiquitylation of HIF-1α	Overexpressed in esophageal squamous cell carcinoma, cervical cancer, and hepatocellular carcinoma	[119,204,205,206]
USP19	Stabilizes HIF-1α and interacts with SIAH1/2 and PHD1/3 regulators	Regulates the proliferation of several prostate and breast cancer cell lines Reduced in human kidney renal clear-cell carcinoma	[121,122,207,208]
USP28	Counteracts Fbw7-mediated HIF-1α ubiquitylation	Depletion can reduce colon cancer in mice Overexpressed in bladder and gastric cancers Reduction promotes liver cancer and correlates with a worse survival of patients with invasive ductal breast carcinoma	[111,114,115,116,117]
USP52	Stabilizes HIF-1α mRNA	Overexpressed in breast carcinomas	[124,209]
OTUD7B	Stabilizes HIF-1α and E2F1 transcription factor to control the expression of HIF-2α mRNA; affects HIF-2α at the transcript level	Reduced expression in hepatocellular carcinoma patients and in lung adenocarcinoma High levels are associated with a good prognosis in patients with nonsmall cell lung cancer Suppresses Akt activation and Kras-driven lung tumorigenesis in mice	[70,125,127,210,211,212,213]