UHRF1 Promotes Cell Growth and Metastasis Through Repression of p16ink4a in Colorectal Cancer

Wang, Rui; Yang, Yongzhi; Shi, Chenzhang; Zhang, Peng; Moyer, Mary Pat; Zhang, Huizhen; Zou, Yang; Qin, Huanlong

doi:10.1245/s10434-011-2194-1

Cited by 88 publications

(120 citation statements)

References 26 publications

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“…At the M phase of the cell cycle, USP7 disassociates from UHRF1, thus exposing UHRF1 to proteasomal degradation (18). Importantly, manipulating the UHRF1 level in cells has been shown to affect cell proliferation (11,18,20). Collectively, these findings suggest that maintaining an appropriate level of UHRF1 is important for processes such as cell proliferation regulation and the DDR.…”

mentioning

confidence: 89%

“…These domains underlie the ability of UHRF1 to play a role in multiple processes, such as maintenance of DNA methylation, heterochromatin organization, and gene transcription (1)(2)(3)(4)(5)(6)(7)(8). Previous studies identified a correlation between UHRF1 overexpression and cancer progression and metastasis, possibly through silencing of various tumor suppressor genes (9)(10)(11)(12). Moreover, UHRF1 is implicated in apoptosis in response to DNA damage.…”

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confidence: 99%

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DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

Chen

Inuzuka

et al. 2013

Molecular and Cellular Biology

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f UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) is a critical epigenetic player involved in the maintenance of DNA methylation patterns during DNA replication. Dysregulation of the UHRF1 level is implicated in cancer onset, metastasis, and tumor recurrence. Previous studies demonstrated that UHRF1 can be stabilized through USP7-mediated deubiquitylation, but the mechanism through which UHRF1 is ubiquitylated is still unknown. Here we show that proteasomal degradation of UHRF1 is mediated by the SCF ␤-TrCP E3 ligase. Through bioinformatic and mutagenesis studies, we identified a functional DSG degron in the UHRF1 N terminus that is necessary for UHRF1 stability regulation. We further show that UHRF1 physically interacts with ␤-TrCP1 in a manner dependent on phosphorylation of serine 108 (S108 UHRF1 ) within the DSG degron. Furthermore, we demonstrate that S108 UHRF1 phosphorylation is catalyzed by casein kinase 1 delta (CK1␦) and is important for the recognition of UHRF1 by SCF ␤-TrCP . Importantly, we demonstrate that UHRF1 degradation is accelerated in response to DNA damage, coincident with enhanced S108 UHRF1 phosphorylation. Taken together, our data identify SCF ␤-TrCP as a bona fide UHRF1 E3 ligase important for regulating UHRF1 steady-state levels both under normal conditions and in response to DNA damage.T he epigenetic regulator UHRF1 is composed of multiple functional domains, including the UBL, Tudor, PHD, SRA, and RING domains, which are responsible for the recognition of histone and DNA methylation as well as ubiquitylation by UHRF1. These domains underlie the ability of UHRF1 to play a role in multiple processes, such as maintenance of DNA methylation, heterochromatin organization, and gene transcription (1-8). Previous studies identified a correlation between UHRF1 overexpression and cancer progression and metastasis, possibly through silencing of various tumor suppressor genes (9-12). Moreover, UHRF1 is implicated in apoptosis in response to DNA damage. Murine embryonic stem cells with targeted disruption of the Uhrf1 gene are hypersensitive to DNA-damaging agents (13). Similarly, knockdown of UHRF1 in HEK293 and WI-38 cells also renders these cells hypersensitive to X rays, UV light, and hydroxyurea (14). More recently, UHRF1 has also been shown to facilitate the DNA damage response (DDR) to gamma irradiation (15, 16). Consistently, DNA damage results in a decrease in the UHRF1 mRNA as well as protein level (1). More recent studies suggest that UHRF1 turnover is controlled by proteasome-mediated degradation. These studies identified the deubiquitylase USP7 in the regulation of the UHRF1 level in vivo (17-19). Specifically, UHRF1 is protected from proteasome-mediated degradation through its association with the deubiquitylase USP7, in a cell cycle-dependent manner. At the M phase of the cell cycle, USP7 disassociates from UHRF1, thus exposing UHRF1 to proteasomal degradation (18). Importantly, manipulating the UHRF1 level in cells has been shown to affect cell proliferation (11,18,20...

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confidence: 89%

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confidence: 99%

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

Chen

Inuzuka

et al. 2013

Molecular and Cellular Biology

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“…[18][19][20] Its downregulation arrested colorectal cancer cells at G0/G1 phase by reducing the levels of cyclins A and D1, and induced p16 INK4A -mediated apoptosis. 21 UHRF1 silencing arrested gall bladder cancer cells at G1/S phase in a p21-dependent pathway and triggered apoptosis by upregulating the expression of promyelocytic leukemia (PML) protein. 22 BALB/c nude mice injected with UHRF1 silenced gastric cancer cells (MKN45-shUHRF1 cells) produced smaller tumors and showed decrease in Ki-67 antigen, the marker of cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics

Sidhu

Capalash

2017

Tumour Biol.

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UHRF1 is a master regulator of epigenome as it coordinates DNA methylation and histone modifications. Compelling evidence suggests a strong link between UHRF1 overexpression and tumorigenesis, substantiating its ability to act as a potential biomarker for cancer diagnosis and prognosis. UHRF1 also mediates repair of damaged DNA that makes cancer cells resistant toward cytocidal drugs. Hence, understanding the molecular mechanism of UHRF1 regulation would help in developing cancer therapeutics. Natural compounds have shown applicability to downregulate UHRF1 leading to growth arrest and apoptosis in cancer cells.

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“…Earlier, we saw that also Wang et al 71 show that UHRF1 is upregulated in colorectal cancer case and facilitates in cell proliferation and metastasis via suppression of p16 nk4 . It is evident that overexpression of CDCA2 leads to repression of p16 nk4 and cell proliferation.…”

Section: Dicationmentioning

confidence: 67%

“…This interaction is basically the inhibition of the degradation of UHRF1. Wang et al 71 also show that UHRF1 is upregulated in colorectal cancer case and facilitates in cell proliferation and metastasis via suppression of p16 nk4 . Similar findings have been made in 72 , 73 & 74 .…”

Section: Dicationmentioning

confidence: 94%

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

Sinha¹

2017

Preprint

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WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stemness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2 nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1 , we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2 nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline's efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3 rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (radial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3 rd order biological hypotheses emerge some of which are confirmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest. KEYWORDS -WNT pathway; porcupine inhibitor ETC-1922159; sensitivity analysis; colorectal cancer; unknown biological hypotheses; combinatorial search space; support vector ranking Conference, from 6-11 August 2017, held Significance WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. Often, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be involved in the pathway. The current work reveals at in silico level, the 3rd order WNT10B associated combinations that might be affected by the admin...

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UHRF1 Promotes Cell Growth and Metastasis Through Repression of p16ink4a in Colorectal Cancer

Cited by 88 publications

References 26 publications

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

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UHRF1 Promotes Cell Growth and Metastasis Through Repression of p16ink4a in Colorectal Cancer

Cited by 88 publications

References 26 publications

DNA Damage Regulates UHRF1 Stability via the SCFβ-TrCP E3 Ligase

DNA Damage Regulates UHRF1 Stability via the SCFβ-TrCP E3 Ligase

UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

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DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase

DNA Damage Regulates UHRF1 Stability via the SCF^β-TrCP E3 Ligase