c-Myc-activated USP2-AS1 suppresses senescence and promotes tumor progression via stabilization of E2F1 mRNA

Li, Bingyan; Guang, Zhang; Wang, Zhongyu; Yang, Yang; Wang, Chenfeng; Fang, Debao; Liu, Kaiyue; Wang, Fang; Mei, Yide

doi:10.1038/s41419-021-04330-2

Cited by 19 publications

(14 citation statements)

References 73 publications

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“…These results suggested that USP2-AS1 might be a hypoxia-regulated oncogenic lncRNA during HNSCC progression. Previously, USP2-AS1 has been reported as a direct target of MYC [ 27 ]. In this study, we knocked down MYC in the HNSCC cell line FaDu and found that USP2-AS1 levels were also decreased upon MYC depletion ( Figure S1 ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, Xiang et al reported 14 hypoxia-regulated lncRNA signatures that could be used for prognosis prediction [ 38 ]. USP2-AS1 has been reported to be possibly regulated by MYC [ 27 ]. As a global transcription factor, MYC regulates the expression of a wide range of genes [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, the mechanism through which USP2-AS1 affects DCAF13 by targeting its substrates should be further explored. Although the overexpression of USP2-AS1 has previously been associated with colorectal cancer and lung cancer progression [ 27 , 45 ], the current study added another level of complexity to the manner in which USP2-AS1 regulates cancer progression.…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia-Regulated lncRNA USP2-AS1 Drives Head and Neck Squamous Cell Carcinoma Progression

Tang

Wang

et al. 2022

Cells

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The role of hypoxia-regulated long non-coding RNA (lncRNA) in the development of head and neck squamous cell carcinoma (HNSCC) remains to be elucidated. In the current study, we initially screened hypoxia-regulated lncRNA in HNSCC cells by RNA-seq, before focusing on the rarely annotated lncRNA USP2 antisense RNA 1 (USP2-AS1). We determined that USP2-AS1 is a direct target of HIF1α and is remarkably elevated in HNSCC compared with matched normal tissues. Patients with a higher level of USP2-AS1 suffered a poor prognosis. Next, loss- and gain-of-function assays revealed that USP2-AS1 promoted cell proliferation and invasion in vitro and in vivo. Mechanically, RNA pulldown and LC–MS/MS demonstrated that the E3 ligase DDB1- and CUL4-associated factor 13 (DCAF13) is one of the binding partners to USP2-AS1 in HNSCC cells. In addition, we assumed that USP2-AS1 regulates the activity of DCAF13 by targeting its substrate ATR. Moreover, the knockdown of DCAF13 restored the elevated cell proliferation and growth levels achieved by USP2-AS1 overexpression. Altogether, we found that lncRNA USP2-AS1 functions as a HIF1α-regulated oncogenic lncRNA and promotes HNSCC cell proliferation and growth by interacting and modulating the activity of DCAF13.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hypoxia-Regulated lncRNA USP2-AS1 Drives Head and Neck Squamous Cell Carcinoma Progression

Tang

Wang

et al. 2022

Cells

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“…Notably, the density ratio between pRb and Rb was not parallel to the E2F1 protein level, indicating that there might be other Rb-independent mechanisms for the regulation of E2F1. In fact, Li et al [ 32 ] have reported that MYC stabilizes the mRNA of E2F1 by activating the lncRNA USP2-AS1, thereby increasing the level of E2F1. Hence, the elevated MYC level by HBx-T81P/S101P/L123S ( Figure 3 D and E) might also be involved in the regulation of E2F1 levels.…”

Section: Resultsmentioning

confidence: 99%

Compartmentalisation of Hepatitis B virus X gene evolution in hepatocellular carcinoma microenvironment and the genotype-phenotype correlation of tumorigenicity in HBV-related patients with hepatocellular carcinoma

Fang

Guo

et al. 2022

Emerging Microbes & Infections

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Hepatitis B virus (HBV) exists as quasispecies (QS). However, the evolutionary characteristics of haplotypes of HBV X gene in the hepatocellular carcinoma (HCC) microenvironment remain unclear. Mutations across X gene are essential for the tumorigenicity of HBV X protein (HBx). However, the functional phenotypes of many mutant HBx remain unknown. This study aims to compare the characteristics of X gene evolution between tumour and non-tumour tissues in HCC patients and investigate the tumorigenic phenotype of HBx harbouring mutation T81P/S101P/L123S. This study included 24 HCC patients. Molecular cloning of X gene was performed to analyse characteristics of haplotypes in liver tissues. HCC cell lines stably expressing wild-type or mutant HBx and subcutaneous tumour xenograft mouse model were used to assess HBx-T81P/S101P/L123S tumorigenicity. The mean heterogeneity of HBV QS across X gene in tumour tissues was lower than that in non-tumour tissues. A location bias was observed in X gene clones with genotype C or D in tumour tissues compared to those with genotype B. Mutations in genotype-C or – D clones were mainly clustered in the dimerization region and aa110-aa140 within the transactivation region. A novel mutation combination at residues 81, 101 and 123 was identified in tumour tissues. Further, HBx-T81P/S101P/L123S promotes cell proliferation and increases genomic instability, which was mediated by MYC. This study elucidates the compartmentalized evolution patterns of HBV X gene between intra tumour and non-tumour tissues in HCC patients and provides a new mechanism underlying HBV-driven hepatocarcinogenesis, suggesting a potential viral marker for monitoring HCC.

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“…Understanding what factors might be preventing or reversing senescence might help to identify therapeutic targets to prevent melanomagenesis. Recent studies have shown the effects of c-Myc-activated USP-AS1 [ 43 ] and ZNF [ 43 ] in bypassing senescence and promoting tumorigenesis. Thus, it would be interesting to evaluate whether keratinocytes enable the secretion of these factors in the presence of oncogenic melanocytes and/or by themselves.…”

Section: Discussionmentioning

confidence: 99%

Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes

Sadangi

Milosavljevic

Castro‐Pérez

et al. 2022

Cancers

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BRAFV600E is the most common mutation driver in melanoma. This mutation is known to cause a brief burst of proliferation followed by growth arrest and senescence, which prevent an uncontrolled cell proliferation. This phenomenon is known as oncogene-induced senescence (OIS) and OIS escape is thought to lead to melanomagenesis. Much attention has been focused on the melanocyte-intrinsic mechanisms that contribute to senescence escape. Additional genetic events such as the loss of tumor suppressor PTEN and/or epigenetic changes that contribute to senescence escape have been described. However, the role of the skin microenvironment—specifically, the role of epidermal keratinocytes—on melanomagenesis is not fully understood. In this study, we employ a microfluidic platform to study the interaction between melanocytes expressing the BRAFV600E mutation as well as keratinocytes and dermal fibroblasts. We demonstrate that keratinocytes suppress senescence-related genes and promote the proliferation of transformed melanocytes. We also show that a keratinocyte-conditioned medium can alter the secretion of both pro- and anti-tumorigenic factors by transformed melanocytes. In addition, we show that melanocytes and keratinocytes from donors of white European and black African ancestry display different crosstalks; i.e., white keratinocytes appear to promote a more pro-tumorigenic phenotype compared with black keratinocytes. These data suggest that keratinocytes exert their influence on melanomagenesis both by suppressing senescence-related genes in melanocytes and by affecting the balance of the melanocyte-secreted factors that favor tumorigenesis.

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c-Myc-activated USP2-AS1 suppresses senescence and promotes tumor progression via stabilization of E2F1 mRNA

Cited by 19 publications

References 73 publications

Hypoxia-Regulated lncRNA USP2-AS1 Drives Head and Neck Squamous Cell Carcinoma Progression

Hypoxia-Regulated lncRNA USP2-AS1 Drives Head and Neck Squamous Cell Carcinoma Progression

Compartmentalisation of Hepatitis B virus X gene evolution in hepatocellular carcinoma microenvironment and the genotype-phenotype correlation of tumorigenicity in HBV-related patients with hepatocellular carcinoma

Role of the Skin Microenvironment in Melanomagenesis: Epidermal Keratinocytes and Dermal Fibroblasts Promote BRAF Oncogene-Induced Senescence Escape in Melanocytes

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