SETDB1-mediated methylation of Akt promotes its
                            K63-linked ubiquitination and activation leading to
                            tumorigenesis

Wang, Guihua; Long, Jie; Gao, Yuan; Zhang, Weina; Han, Fei; Xu, Chuan; Sun, Li; Yang, Shung Haur; Lan, Jingqin; Hou, Zhenlin; Zhang, Cai; Jin, Guoxiang; Hsu, Che Chia; Wang, Yu Hui; Hu, Junbo; Chen, Tsai-Yu; Li, Hongyu; Lee, Min Gyu; Lin, Hui Kuan

doi:10.1038/s41556-018-0266-1

Cited by 138 publications

(150 citation statements)

References 37 publications

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“…For histology analysis, the tumors and tissues were fixed in 10% formalin, embedded in paraffin, sectioned and then performed hematoxylin and eosin (H&E) staining or immunohistochemistry staining by standard procedures 33 . The sectioned slides were antigen retrieved (0.01 M Citrate buffer, pH 6.0), incubated with the primary antibody for overnight at 4°C and then detected by VECTASTAIN Universal Quick HRP Kit (Peroxidase) (Vector Laboratory) with DAB kits (Abcam).…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Identification of primordial germ cell-like cells as liver metastasis initiating cells in mouse tumour models

Zhang

et al. 2020

Cell Discov

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Liver metastasis, characterized by the spread of tumors to the liver from other areas, represents a deadly disease with poor prognosis. Currently, there is no effective therapeutic strategies and/or agents to combat liver metastasis primarily due to the insufficient understanding of liver metastasis. To develop a promising strategy for targeting liver metastasis, understanding of a cell origin responsible for liver metastasis and how this cell can be pharmacologically eliminated are therefore crucial. Using diverse tumor models including p53 −/− genetic mouse model and syngeneic tumor models, we identified primordial germ cell (PGC)-like tumor cells, which are enriched in earliest liver micrometastasis (up to 99%), as a cell origin of liver metastasis. PGC-like tumor cells formed earliest micro-metastasis in liver and gradually differentiated into non-PGC-like tumor cells to constitute late macro-metastasis in the course of tumor metastasis. The liver metastasis-initiating cells (PGC-like tumor cells) display cell renewal and differentiation capabilities, resemble primordial germ cells (PGCs) in morphology and PGC marker gene expression, and express higher level of the genes linked to metastasis and immune escape compared with non-PGC-like tumor cells. Of note, Stellar high PGClike tumor cells, but not Stellar low non-PGC-like cells, sorted from primary tumors of p53 −/− mice readily form liver metastasis. Depletion of PGC-like tumor cells through genetic depletion of any of key germ cell genes impairs liver metastasis, while increased PGC-like tumor cells by SMAD2 knockout is correlated with markedly enhanced liver metastasis. Finally, we present the proof of principle evidence that pharmacologically targeting BMP pathways serves as a promising strategy to eliminate PGC-like tumor cells leading to abrogating liver metastasis. Collectively, our study identifies PGC-like tumor cells as a cell origin of liver metastasis, whose depletion by genetically targeting core PGC developmental genes or pharmacologically inhibiting BMP pathways serves a promising strategy for targeting liver metastasis.

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Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Identification of primordial germ cell-like cells as liver metastasis initiating cells in mouse tumour models

Zhang

et al. 2020

Cell Discov

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“…The heterogeneity of the tumors, an incomplete understanding of HCC pathogenesis mechanism, and the lack of efficiency of targeted therapy limit the prognosis of HCC 6 . The occurrence and development of HCC is a complex process, including hepatocyte death, inflammation, fibrosis, cirrhosis, cycles of cell death and compensatory hepatocyte proliferation 7 . Thus, it is essential to underscore different intracellular signals of hepatocarcinogenesis and find multi‐targets active natural compounds to improve current HCC treatment modality.…”

Section: Introductionmentioning

confidence: 99%

HTBPI, an active phenanthroindolizidine alkaloid, inhibits liver tumorigenesis by targeting Akt

Liu

Chen

et al. 2020

FASEB j.

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Akt, a crucial protein involved in a variety of signaling pathways in cancer, acts as an important regulator of survival in hepatocellular carcinoma (HCC), and provides curative option for the related drugs development. We have found an active phenanthroindolizidine alkaloid, (13aR,14R)‐9,11,12,13,13a,14‐hexahydro‐3,6,7‐trimethoxydibenzo[f,h]pyrrolo[1,2‐b]isoquinolin‐14‐ol (HTBPI), is a promising Akt inhibitor effective in the suppression of HCC cells proliferation through stimulating apoptotic and autophagic capability in vivo and in vitro. Treatment of HTBPI combined with a classical autophagy‐lysosomal inhibitor (bafilomycin A1), could enhance stimulation effects of apoptosis on HCC cell lines. In addition, we confirmed HTBPI targeting Akt, occupied the kinase binding domain (Thr 308) of Akt to inactivate its function by CETSA and DARTS assay. In contrast, ectopic Akt‐induced overexpression significantly abrogated inhibitory effects of HTBPI on cell viability and proliferation. Furthermore, high p‐Akt (Thr 308) expression is collated with liver tumor formation and poor survival in HCC patients. In conclusions, HTBPI impeded HCC progress through regulation of apoptosis and autophagy machinery via interaction with p‐Akt (Thr 308). This may provide potential molecular candidate by targeting Akt for the therapy of HCC patients.

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“…7,9,15,16 In this study, the anomalous expression pattern of SKP2 in RB tissues and cell lines were observed. 7,9,15,16 In this study, the anomalous expression pattern of SKP2 in RB tissues and cell lines were observed.…”

Section: Discussionmentioning

confidence: 61%

SKP2, positively regulated by circ_ODC1/miR‐422a axis, promotes the proliferation of retinoblastoma

Wang

Zhang

et al. 2019

J of Cellular Biochemistry

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Retinoblastoma (RB) is the most common intraocular malignancy in infants and children. S‐phase kinase‐associated protein 2 (SKP2) has been unmasked as an oncogene in a great many of carcinomas. The biologic function and the detailed molecular mechanism of SKP2 in RB need to be better understood. In this study, real‐time quantitative polymerase chain reaction and Western blot showed the ectopic expression of SKP2 in RB tissues and cell lines. Loss of function assays showed the attenuated cell proliferation in RB as a result of SKP2 knockdown. In addition, bioinformatics analysis predicted the interaction between SKP2 and miR‐422a. Luciferase reporter assay and Pearson's correlation analysis validated the negative correlation between miR‐422a and SKP2. MiR‐422a overexpression led to a decline of SKP2 expression and cell growth in RB. The binding capacity between miR‐422a and circ_ODC1 was also predicted by bioinformatics analysis. Pearson's correlation analysis and luciferase reporter assay confirmed that circ_ODC1 is negatively correlated with miR‐422a. Silencing circ_ODC1 resulted in a rise in miR‐422a expression and RB cell growth. Moreover, reduced cell growth was restored by SKP2 overexpression. In a word, SKP2, induced by circ_ODC1 and miR‐422a, promotes RB proliferation. Our new findings in this research might expedite the discovery of novel prognostic markers and therapeutic targets of RB.

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SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis

Cited by 138 publications

References 37 publications

Identification of primordial germ cell-like cells as liver metastasis initiating cells in mouse tumour models

Identification of primordial germ cell-like cells as liver metastasis initiating cells in mouse tumour models

HTBPI, an active phenanthroindolizidine alkaloid, inhibits liver tumorigenesis by targeting Akt

SKP2, positively regulated by circ_ODC1/miR‐422a axis, promotes the proliferation of retinoblastoma

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