A new layer of degradation mechanism for PR-Set7/Set8 during cell cycle

Zheng, Nana; Dai, Xiangpeng; Wang, Zhiwei; Wei, Wenyi

doi:10.1080/15384101.2016.1234552

Cited by 6 publications

(4 citation statements)

References 90 publications

(117 reference statements)

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“…Protein ubiquitination and deubiquitination are involved in the regulation of virtually all aspects of cellular biology, with effects ranging from altered protein stability to changes in protein function. Several E3 ligases have been reported to promote the ubiquitination and degradation of SET8 (7). In contrast, the DUB(s) of SET8 require further investigation.…”

Section: Discussionmentioning

confidence: 99%

The ubiquitin-specific protease USP17 prevents cellular senescence by stabilizing the methyltransferase SET8 and transcriptionally repressing p21

Fukuura

Inoue

Miyajima

et al. 2019

Journal of Biological Chemistry

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Edited by Xiao-Fan Wang Su(var)3-9, Enhancer-of-zeste, and Trithorax (SET) domaincontaining protein 8 (SET8) is the sole enzyme that monomethylates Lys-20 of histone H4 (H4K20). SET8 has been implicated in the regulation of multiple biological processes, such as gene transcription, the cell cycle, and senescence. SET8 quickly undergoes ubiquitination and degradation by several E3 ubiquitin ligases; however, the enzyme that deubiquitinates SET8 has not yet been identified. Here we demonstrated that ubiquitinspecific peptidase 17-like family member (USP17) deubiquitinates and therefore stabilizes the SET8 protein. We observed that USP17 interacts with SET8 and removes polyubiquitin chains from SET8. USP17 knockdown not only decreased SET8 protein levels and H4K20 monomethylation but also increased the levels of the cyclin-dependent kinase inhibitor p21. As a consequence, USP17 knockdown suppressed cell proliferation. We noted that USP17 was down-regulated in replicative senescence and that USP17 inhibition alone was sufficient to trigger cellular senescence. These results reveal a regulatory mechanism whereby USP17 prevents cellular senescence by removing ubiquitin marks from and stabilizing SET8 and transcriptionally repressing p21. Su(var)3-9, Enhancer-of-zeste, and Trithorax (SET) 5 domaincontaining protein 8 (SET8) (also known as SETD8, PR-Set7, and KMT5A) is the sole enzyme required to catalyze monomethylation of histone H4 lysine 20 (H4K20me1) (1-3). Besides H4K20me1, SET8 can methylate nonhistone proteins, including p53, proliferating cell nuclear antigen, Numb, and androgen receptor and estrogen receptor ␣ (4). SET8 is involved in vital cellular processes such as DNA replication, mitosis, DNA repair, and gene transcriptional regulation (5, 6). Therefore, precise modulation of SET8 levels is important for proper cell cycle regulation, and deregulation of SET8 expression has been suggested to cause cellular transformation and contribute to cancer progression (7). Aberrant expression of SET8 has been detected in many types of tumors (8-11). High levels of SET8 are also associated with poor survival in cancer patients (9-11). Moreover, recent studies have shown that SET8 prevents cellular senescence through epigenetic regulation (12, 13). Loss of SET8 is sufficient to establish cellular senescence, and H4K20me1 modification of the cyclin-dependent kinase inhibitor p21 gene during cellular senescence is regulated by SET8 (12, 13). Because knockdown of p21 alleviates the senescence state of SET8 knockdown cells, SET8 suppresses induction of cellular senescence by repressing p21 transcription (13). SET8 is regulated at several levels, including the transcriptional level (14), posttranscriptional level (15), and posttranslational level (7). Some E3 ubiquitin ligases have been shown to induce SET8 ubiquitination and degradation, which regulate cell cycle progression (7). The anaphase-promoting complex APC/C Cdh1 induces ubiquitination and degradation of SET8 during G 1 phase (16). In addition, Cullin-RING ubiquitin ...

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Section: Discussionmentioning

confidence: 99%

The ubiquitin-specific protease USP17 prevents cellular senescence by stabilizing the methyltransferase SET8 and transcriptionally repressing p21

Fukuura

Inoue

Miyajima

et al. 2019

Journal of Biological Chemistry

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“…SET8 protein expression is tightly regulated during the cell cycle, and SET8 homozygous null mutant embryos displayed early lethality due to cell-cycle defects and improper mitotic chromosome condensation, reflecting its essential roles in the proper progression of the cell cycle 22 . The dysregulation of SET8 expression has been implicated in many disease conditions, including cancer 22,23 . SET8 overexpression has been detected in various types of tumors and associated with the poor survival rate of cancer patients [24][25][26] .…”

Section: Set8 Is a Novel Negative Regulator Of Tgf-β Signaling In A M...mentioning

confidence: 99%

SET8 is a novel negative regulator of TGF-β signaling in a methylation-independent manner

Nagasaka,

Inoue,

Nagao

et al. 2023

Sci Rep

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Transforming growth factor β (TGF-β) is a multifunctional cytokine that induces a diverse set of cellular processes principally through Smad-dependent transcription. Transcriptional responses induced by Smads are tightly regulated by Smad cofactors and histone modifications; however, the underlying mechanisms have not yet been elucidated in detail. We herein report lysine methyltransferase SET8 as a negative regulator of TGF-β signaling. SET8 physically associates with Smad2/3 and negatively affects transcriptional activation by TGF-β in a catalytic activity-independent manner. The depletion of SET8 results in an increase in TGF-β-induced plasminogen activator inhibitor-1 (PAI-1) and p21 expression and enhances the antiproliferative effects of TGF-β. Mechanistically, SET8 occupies the PAI-1 and p21 promoters, and a treatment with TGF-β triggers the replacement of the suppressive binding of SET8 with p300 on these promoters, possibly to promote gene transcription. Collectively, the present results reveal a novel role for SET8 in the negative regulation of TGF-β signaling.

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“…As consequence, G1/S transition is blocked and the cell cycle stopped [ 69 ]. In MCF7 and MDA-MB231 breast cancer cell lines, USP17 knockdown also led to a decrease in SET (Su(var)3-9, enhancer of zeste and trithorax) domain-containing protein 8 (SET8) levels, resulting in the suppression of cell proliferation due to the increase in p21 levels [ 68 , 70 ]. Another study demonstrated that ectopic expression of USP17 in HEK293T cells led to deubiquitination of the ELK1 transcription factor that is involved in ERK (extracellular-signal-regulated kinase) signaling.…”

Section: Association Of Ubiquitin-specific Proteases (Usps) With Cancer-related Processesmentioning

confidence: 99%

Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

2021

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Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.

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A new layer of degradation mechanism for PR-Set7/Set8 during cell cycle

Cited by 6 publications

References 90 publications

The ubiquitin-specific protease USP17 prevents cellular senescence by stabilizing the methyltransferase SET8 and transcriptionally repressing p21

The ubiquitin-specific protease USP17 prevents cellular senescence by stabilizing the methyltransferase SET8 and transcriptionally repressing p21

SET8 is a novel negative regulator of TGF-β signaling in a methylation-independent manner

Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

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