USP22 upregulates ZEB1-mediated VEGFA transcription in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a common solid tumor with high rate of recurrence and mortality. Anti-angiogenesis drugs have been used for the therapy of HCC. However, anti-angiogenic drug resistance commonly occurs during HCC treatment. Thus, identification of a novel VEGFA regulator would be better understanding for HCC progression and anti-angiogenic therapy resistance. Ubiquitin specific protease 22 (USP22) as a deubiquitinating enzyme, participates in a variety of biological processes in numerous tumors. While the molecular mechanism underlying the effects of USP22 on angiogenesis is still needed to be clarified. Here, our results demonstrated that USP22 acts as a co-activator of VEGFA transcription. Importantly, USP22 is involved in maintenance of ZEB1 stability via its deubiquitinase activity. USP22 was recruited to ZEB1-binding elements on the promoter of VEGFA, thereby altering histone H2Bub levels, to enhance ZEB1-mediated VEGFA transcription. USP22 depletion decreased cell proliferation, migration, Vascular Mimicry (VM) formation, and angiogenesis. Furthermore, we provided the evidence to show that knockdown of USP22 inhibited HCC growth in tumor-bearing nude mice. In addition, the expression of USP22 is positively correlated with that of ZEB1 in clinical HCC samples. Our findings suggest that USP22 participates in the promotion of HCC progression, if not all, at least partially via up-regulation of VEGFA transcription, providing a novel therapeutic target for anti-angiogenic drug resistance in HCC.

Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation

“…Over the past 3 years, the deubiquitination ZEB1 has been intensively studied in various solid tumors. Several DUBs, including USP10, USP18, USP22, USP43, and USP51 have been identified as key regulators of ZEB1 stability, thereby promoting proliferation, migration and invasion of cancer cells across different malignancies [26], [50], [51], [52], [53], [54]. Our study confirms this findings, demonstrating that the regulation of ZEB1 by DUBs constitutes a general mechanism driving cancer cells aggressiveness, which extends to hematological malignancies capable of acquiring EMT-like marker features, such as MM.…”

SPHK1 promotes the migration and invasion of gastric cancer cells through NF-κB pathway

“…PDTC(inhibitor of NF-κB pathway) [32,33] was used to interfere with SPHK1 knockdown and overexpression cell lines, and the results showed that SPHK1 weakened the migration and invasion of GC cells, suggesting that NF-κB was involved in SPHK1-mediated migration and invasion of GC cells. VEGFA is an important angiogenic factor associated with GC invasion and metastasis [34,35]. IL-17 works with immune cells to promote tumor metastasis [36].…”

Ubiquitin-specific protease 21 promotes tumorigenicity and stemness of colorectal cancer by deubiquitinating and stabilizing ZEB1

“…Furthermore, ZEB1 reduces SLC3A2 to strengthen chemoresistance to cisplatin in ovarian cancer[ 22 ]. Interestingly, USP22 exhibits deubiquitinase activity to affect the maintenance of ZEB1 stability[ 23 ]. Therefore, we suspected that USP21 can also regulate ZEB1 ubiquitination and stability.…”