Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis

Heo, Jinbeom; Noh, Byeong‐Joo; Lee, Seungun; Lee, Hye‐Yeon; Kim, YongHwan; Lim, Jisun; Ju, Hyein; Yu, Hwan Yeul; Ryu, Chae‐Min; Lee, Peter Cw; Jeong, Hee Jong; Oh, Yumi; Kim, Kyunggon; Kim, Sangjin; Son, Jaekyoung; Hong, Bumsik; Kim, Jong Soo; Cho, Yong Mee; Shin, Dong‐Myung

doi:10.15252/emmm.201910880

Cited by 57 publications

(65 citation statements)

References 64 publications

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“…Identifying novel mechanisms underlying the maintenance of the stemness of CSCs is one of the most important work for developing novel therapeutic strategies [25]. Although it was previously reported that SCF complexes plays a crucial role in cancer development, few was known about its role in CSCs [26]. In this study, we found that overexpression of SKP1 promotes the stemness of CRC-SCs and knockdown of SKP1 leads to the opposite results.…”

Section: Discussionmentioning

confidence: 67%

SKP1 promotes YAP-mediated colorectal cancer stemness via suppressing RASSF1

Tian

Lang

Qiu

et al. 2020

Preprint

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Background: Cancer stem cells have been recognized as an important drug target, however, the mechanisms underlying the maintenance of cancer stem cells have not been fully understood. SKP1 is a traditional drug target for cancer therapy, while, whether SKP1 could be a target for eradicating cancer stem cells remains elusive.Methods: Human colorectal cancer cell lines HCT-116 and HT-29 and primary human colorectal cancer cells were used in this study. Gene manipulation was performed by lentivirus system. The mRNA and protein levels were examined by qRT-PCR and western blot, respectively. Sphere formation and transwell assay were employed for examination of sphere-forming and migration capacities. The tumorigenicity was examined by xenograft model. The transcriptional activities of the promoters were examined by luciferase reporter assay. Co-immunoprecipitation assay was used to test protein-protein interaction. The relationship between gene expression and survival was analyzed by Kaplan-meier analysis. The correlation between two genes was analyzed by Spearman analysis. Data are represented as mean ± s.d. and the significance was determined by Student’s t-test.Results: SKP1 is upregulated in colorectal cancer stem cells and predicts poor prognosis of colon cancer patients. Overexpression of SKP1 promotes the sphere-forming and migration capacities of colorectal cancer stem cells, and upregulates the expression of cancer stem cell markers. In contrast, SKP1 depletion produces the opposite effects. SKP1 strengthens YAP activity and knockdown of YAP abolished the effect of SKP1 on the stemness of colorectal cancer cells. SKP1 suppresses RASSF1 at both mRNA and protein levels and overexpression of RASSF1 abolished the effect of SKP1.Conclusion: In summary, our results demonstrated that SKP1 suppresses RASSF1 at both mRNA and protein level, attenuates Hippo signaling, activates YAP, and thereby promoting the stemness of colorectal cancer stem cells. Our works thus revealed a novel underlying mechanism of colorectal cancer stem cell maintenance and suggested a novel drug target for eradicating colorectal cancer stem cells.

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Section: Discussionmentioning

confidence: 67%

SKP1 promotes YAP-mediated colorectal cancer stemness via suppressing RASSF1

Tian

Lang

Qiu

et al. 2020

Preprint

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“…Activation of the CDK1-TFCP2L1 pathway stimulated cell proliferation, self-renewal and invasion in human aggressive bladder cancer. 31 Deng 32 reported that the up-regulation of CDK1 inhibited the G2/M phase block and promoted cervical cancer resistance to radiotherapy. CDK1 was also found to be stably activated by CDK1-KCTD12 interaction in BRAF-mutated colon cancer models resistant to Vemurafenib.…”

Section: Discussionmentioning

confidence: 99%

<p>Inhibition of CDK1 Reverses the Resistance of 5-Fu in Colorectal Cancer</p>

Zhu

Zhang

et al. 2020

CMAR

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Introduction: Although the survival rate of colorectal cancer (CRC) patients can be improved by surgery, radiotherapy, and chemotherapy, the resistance to 5-fluorouracil (5-Fu) affects the effect of chemotherapy and the prognosis of patients. An increasing number of studies showed that 5-Fu resistance was the main reason for the failure of colorectal cancer treatment. The poor prognosis of colorectal cancer greatly harms people's health. This study aimed to clarify the correlation between cyclin-dependent kinase 1 (CDK1) and 5-Fu-induced tumor resistance. Materials and Methods: Cell proliferation and invasion experiments showed that downregulation of CDK1 inhibited fluorouracil-resistant CRC cell proliferation. The expression level of CDK1 was detected in 5-Fu-resistant CRC cells in vitro. Tumor growth was inhibited by down-regulation of CDK1 in tumor xenograft mouse models. Results: We found that CDK1 was highly expressed in tumor tissues, especially in fluorouracil-resistant tissues. We also confirmed that the differential expression of 5-Fu in tumor tissues was related to tumor site, lymph node metastasis and stage. CDK1 promoted migration, invasion and inhibited apoptosis in 5-Fu-resistant CRC cells. Down-regulation of CDK1 inhibited fluorouracil-resistant CRC cell proliferation and tumorigenesis in vivo. Conclusion: High expression of CDK1 may lead to poor clinical prognosis, and inhibition of CDK1 enhances 5-Fu sensitivity in CRC. Our research suggested that CDK1 may be used to predict 5-Fu efficacy and as a therapeutic target for CRC.

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“…All M-MSCs were expanded for less than ten passages to ensure multipotency. To induce stable GFP expression, M-MSCs were infected with a GFP-expressing lentivirus, which was generated as described previously [ 28 , 29 ]. M-MSCs were infected with concentrated lentivirus containing a GFP expression construct using 6 µg/mL polybrene (Invitrogen, Carlsbad, CA, USA), and infected cells were selected using 6 µg/mL blasticidin (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Therapeutic Efficacy of Human Embryonic Stem Cell-Derived Multipotent Stem/Stromal Cells in Diabetic Detrusor Underactivity: A Preclinical Study

Shin

Ryu

et al. 2020

JCM

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Mesenchymal stem/stromal cell (MSC) therapy is a promising approach for treatment of as yet incurable detrusor underactivity (DUA), which is characterized by decreased detrusor contraction strength and/or duration, leading to prolonged bladder emptying. In the present study, we demonstrated the therapeutic potential of human embryonic stem cell (ESC)-derived multipotent MSCs (M-MSCs) in a diabetic rat model of DUA. Diabetes mellitus (DM) was induced by intraperitoneal injection of streptozotocin (STZ) (50 mg/kg) into 8-week-old female Sprague-Dawley rats. Three weeks later, various doses of M-MSCs (0.25, 0.5, and 1 × 106 cells) or an equivalent volume of PBS were injected into the outer layer of the bladder. Awake cystometry, organ bath, histological, and gene expression analyses were evaluated 1 week (short-term) or 2 and 4 weeks (long-term) after M-MSC transplantation. STZ-induced diabetic rats developed DUA, including phenotypes with significantly longer micturition intervals, increased residual urine amounts and bladder capacity, decreased micturition pressure on awake cystometry, and contractile responses to various stimuli in organ bath studies. Muscle degeneration, mast cell infiltration, fibrosis, and apoptosis were present in the bladders of DM animals. A single local transplantation of M-MSCs ameliorated DUA bladder pathology, including functional changes and histological evaluation, and caused few adverse outcomes. Immunostaining and gene expression analysis revealed that the transplanted M-MSCs supported myogenic restoration primarily by engrafting into bladder tissue via pericytes, and subsequently exerting paracrine effects to prevent apoptotic cell death in bladder tissue. The therapeutic efficacy of M-MSCs was superior to that of human umbilical cord-derived MSCs at the early time point (1 week). However, the difference in efficacy between M-MSCs and human umbilical cord-derived MSCs was statistically insignificant at the later time points (2 and 4 weeks). Collectively, the present study provides the first evidence for improved therapeutic efficacy of a human ESC derivative in a preclinical model of DM-associated DUA.

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Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis

Cited by 57 publications

References 64 publications

SKP1 promotes YAP-mediated colorectal cancer stemness via suppressing RASSF1

SKP1 promotes YAP-mediated colorectal cancer stemness via suppressing RASSF1

<p>Inhibition of CDK1 Reverses the Resistance of 5-Fu in Colorectal Cancer</p>

Therapeutic Efficacy of Human Embryonic Stem Cell-Derived Multipotent Stem/Stromal Cells in Diabetic Detrusor Underactivity: A Preclinical Study

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