FOXO1 degradation via G9a-mediated methylation promotes cell proliferation in colon cancer

Chae, Yun-Cheol; Kim, Jiyoung; Park, Jin Woo; Kim, Kee-Beom; Oh, Hyein; Lee, Kyung‐Hwa; Seo, Sang-Beom

doi:10.1093/nar/gky1230

Cited by 104 publications

(76 citation statements)

References 54 publications

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“…Forkhead transcription factors are characterized by a winged helix DNA-binding domain and are essential for embryogenesis (Kaufmann and Knöchel, 1996). Some of them, such as FOXQ1, FOXQ3 and FOXO1, have been identified as regulating tumorigenesis and tumor progression (Mottok et al, 2018;Saito et al, 2016;Chae et al, 2019). It has been reported that the Forkhead box F2 transcription factor (FOXF2) functions as tumor suppressor in breast cancer, gastric cancer, colorectal cancer, lung cancer and hepatocellular carcinoma (Cai et al, 2015;Higashimori et al, 2018;Zhang et al, 2015;Kundu et al, 2016;Shi et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-96-5p promotes proliferation, invasion and EMT of oral carcinoma cells by directly targeting FOXF2

Wang

et al. 2020

Biology Open

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Recently, microRNA-96-5p (miR-96-5p) has been reported to function as both a tumor suppressor and oncogene in several cancer types, including gastric cancer, hepatocellular cancer and lung cancer. However, the biological function of miR-96-5p and its precise mechanisms in oral squamous cell carcinoma (OSCC) have not been well clarified. The aim of this study was to study the roles of miR-96-5p/ FOXF2 axis in OSCC. In this study, the miR-96-5p level was dramatically enhanced in OSCC tissues and cell lines, and the FOXF2 expression was significantly reduced. In addition, the FOXF2 expression was negatively related to the miR-96-5p level in OSCC tissues. Furthermore, downregulation of miR-96-5p obviously restrained OSCC cell proliferation, invasion and EMT. We confirmed that miR-96-5p could directly target FOXF2 by luciferase reporter assay. Moreover, knockdown of FOXF2 also could markedly promote the proliferation, invasion and EMT of OSCC cells. Finally, overexpression of FOXF2 in OSCC cells partially reversed the promoted effects of miR-96-5p mimic. Knockdown of miR-96-5p restrained OSCC cells proliferation, invasion and EMT via regulation of FOXF2.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-96-5p promotes proliferation, invasion and EMT of oral carcinoma cells by directly targeting FOXF2

Wang

et al. 2020

Biology Open

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“…G9a functions as a histone methyltransferase (HMTase), modulating the methylation of histones H3K9 and H3K27 [7,8]. H3K9 methylation controlled by G9a is an essential process of transcriptional repression of many related genes during cancer development [9][10][11][12][13][14]. There has been an increasing amount of evidence regarding the role of G9a in tumorigenesis [15,16].…”

Section: Introductionmentioning

confidence: 99%

“…There has been an increasing amount of evidence regarding the role of G9a in tumorigenesis [15,16]. G9a is unregulated in various cancers, including human bladder [17,18], lung [19][20][21], colon [9,22] and breast cancer [14,[23][24][25][26], compared with normal tissue. G9a also contributes to the inhibition of E-cadherin expression in ovarian and endometrial cancer [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Abnormal overexpression of G9a in melanoma cells promotes cancer progression via upregulation of the Notch1 signaling pathway

Jiao

Meng

et al. 2020

Aging

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Malignant melanoma is a type of very dangerous skin cancer. Histone modifiers usually become dysregulated during the process of carcinoma development, thus there is potential for a histone modifier inhibitor as a useful drug for cancer therapy. There is a multitude of evidence regarding the role of G9a, a histone methyltransferase (HMTase), in tumorigenesis. In this study, we first showed that G9a was significantly upregulated in melanoma patients. Using the TCGA database, we found a significantly higher expression of G9a in primary melanoma samples (n = 461) compared to normal skin samples (n = 551). Next, we knocked down G9a in human M14 and A375 melanoma cell lines in vitro via small interfering RNA (siRNA). This resulted in a significant decrease in cell viability, migration and invasion, and an increase in cell apoptosis. UNC0642 is a small molecule inhibitor of G9a that demonstrates minimal cell toxicity and good in vivo pharmacokinetic characteristics. We investigated the role of UNC0642 in melanoma cells, and detected its anti-cancer effects in vitro and in vivo. Next, we treated cells with UNC0642, and observed a significant decrease in cell viability in M14 and A375 cell lines. Furthermore, treatment with UNC0642 resulted in increased apoptosis. In immunocompetent mice bearing A375 engrafts, treatment with UNC0642 inhibited tumor growth. Results of Western blot analysis revealed that administration of UNC0642 or silencing of G9a expression by siRNA reduced Notch1 expression significantly and decreased the level of Hes1 in A375. All in all, the data from our study demonstrates potential of G9a as a therapeutic target in the treatment of melanoma.

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“…FOXO1 as a tumor suppressor has been associated with multiple types of malignancies, including colon, cervical, prostate, gastric, and breast cancers (40, 44-47). Based on our findings that USP7 deubiquitinated H2BK120ub1 and recruited the PRC2 complex to suppress the transcription of FOXO1, we postulated that the USP7/EZH2-FOXO1 signaling pathway plays an important role in carcinogenesis.…”

Section: Resultsmentioning

confidence: 99%

Bimodal Regulation of the PRC2 Complex by USP7 Underlies Melanomagenesis

Wang

Hou³

et al. 2019

Preprint

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Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in melanoma cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation.Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives melanoma cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during melanoma progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of melanoma patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for melanoma.

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FOXO1 degradation via G9a-mediated methylation promotes cell proliferation in colon cancer

Cited by 104 publications

References 54 publications

MicroRNA-96-5p promotes proliferation, invasion and EMT of oral carcinoma cells by directly targeting FOXF2

MicroRNA-96-5p promotes proliferation, invasion and EMT of oral carcinoma cells by directly targeting FOXF2

Abnormal overexpression of G9a in melanoma cells promotes cancer progression via upregulation of the Notch1 signaling pathway

Bimodal Regulation of the PRC2 Complex by USP7 Underlies Melanomagenesis

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