Journal
CANCER LETTERS
Volume 514, Issue -, Pages 63-78Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.05.015
Keywords
Hepatocellular carcinoma; USP11; Autophagy
Categories
Funding
- National Natural Science Foundation of China [81903013]
- Science and Technology Innovation Commission of Shenzhen [KQJSCX20180321164801762]
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USP11 interacts with E2F1 to promote proliferation and metastasis of HCC cells while inhibiting autophagy. Combination treatment targeting USP11 and autophagy enhances apoptosis of HCC cells and inhibits tumor growth effectively. This suggests the potential of E2F1/USP11 as a therapeutic target in HCC.
Deubiquitinase ubiquitin-specific protease 11 (USP11), a member of the deubiquitinating family, plays an important but still controversial role in cancer development. Namely, USP11 has been shown to promote the proliferation and metastasis of hepatocellular carcinoma (HCC), but the underlying molecular basis is poorly understood. This study aimed to unravel novel functions of USP11 in HCC, especially those related to autophagy. Here, EdU, migration and colony formation assays, and mouse models showed that USP11 played a crucial role in HCC cell proliferation and metastasis in vitro and in vivo. Results from co-immunoprecipitation and ubiquitination assays demonstrated that USP11 interacted with E2F1 and maintained E2F1 protein stability by removing its ubiquitin. Notably, E2F1 regulated USP11 expression at the transcriptional level. Thus, the E2F1/USP11 formed a positive feedback loop to promote the proliferation and migration of HCC cells. Moreover, E2F1/USP11 inhibited autophagy by regulating ERK/mTOR pathway. In addition, the combination treatment inhibition of USP11 and autophagy enhanced the apoptosis of HCC cells and inhibited the tumor growth in mice more effective than either treatment alone. Taken together, these results indicate that the E2F1/USP11 signal axis promotes HCC proliferation and metastasis and inhibits autophagy, which provides an experimental basis for the treatment of HCC.
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