MBD3 inhibits formation of liver cancer stem cells

Li, Ruizhi; He, Qihua; Han, Shuo; Zhang, Mingzhi; Liu, Jinwen; Su, Ming; Wei, Shiruo; Wang, Xuan; Shen, Li

doi:10.18632/oncotarget.13496

Cited by 14 publications

(13 citation statements)

References 31 publications

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“…Overall, our findings indicate a tumor suppressor function of MBD3, a subunit of the NuRD complex, in human myeloid leukemia. Gut‐specific conditional inactivation of Mbd3 causes increased susceptibility to tumorigenesis, highlighting its tumor suppressor role (52, 53). Loss of MBD3 has been also linked with pancreatic cancer cell invasion and metastasis (54).…”

Section: Discussionmentioning

confidence: 99%

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

et al. 2019

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Cancer genome sequencing studies have focused on identifying oncogenic mutations. However, mutational profiling alone may not always help dissect underlying epigenetic dependencies in tumorigenesis. Nucleosome remodeling and deacetylase (NuRD) is an ATP‐dependent chromatin remodeling complex that regulates transcriptional architecture and is involved in cell fate commitment. We demonstrate that loss of MBD3, an important NuRD scaffold, in human primary acute myeloid leukemia (AML) cells associates with leukemic NuRD. Interestingly, CHD4, an intact ATPase subunit of leukemic NuRD, coimmunoprecipitates and participates with H3K27Me3/2‐demethylase KDM6A to induce expression of atypical guanine nucleotide exchange factors, dedicator of cytokinesis (DOCK) 5 and 8 (DOCK5/8), promoting Rae GTPase signaling. Mechanistically, MBD3 deficiency caused loss of histone deacytelase 1 occupancy with a corresponding increase in KDM6A, CBP, and H3K27Ac on DOCK5/8 loci, leading to derepression of gene expression. Importantly, the Cancer Genome Atlas AML cohort reveals that DOCK5/8 levels are correlated with MBD3 and KDM6A, and DOCK5/8 expression is significantly increased in patients who are MBD3 low and KDM6A high with a poor survival. In addition, pharmacological inhibition of DOCK signaling selectively attenuates AML cell survival. Because MBD3 and KDM6A have been implicated in metastasis, our results may suggest a general phenomenon in tumorigenesis. Collectively, these findings provide evidence for MBD3‐deficient NuRD in leukemia pathobiology and inform a novel epistasis between NuRD and KDM6A toward maintenance of oncogenic gene expression in AML.—Biswas, M., Chatterjee, S. S., Boila, L. D., Chakraborty, S., Banerjee, D., Sengupta, A. MBD3/NuRD loss participates with KDM6A program to promote DOCK5/8 expression and Rae GTPase activation in human acute myeloid leukemia. FASEB J. 33, 5268–5286 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

et al. 2019

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“…The investigation of CD44 helps to understand the molecular mechanism underlying liver iCSCs. Former studies of our lab find that CD44 is overexpressed in the nucleus of C3A-iCSCs, shMBD3-iCSCs and C3A-c-Jun-iCSCs 20, 21. This phenomenon caused our great concern.…”

Section: Introductionmentioning

confidence: 99%

Nuclear CD44 Mediated by Importin β Participated in Naïve Genes Transcriptional Regulation in C3A-iCSCs

Su¹,

Wang²,

Wang³

et al. 2019

Int. J. Biol. Sci.

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CD44 is one of biomarkers of liver cancer stem cells (CSCs). The investigation of mechanism of CD44 translocation helps to uncover new molecular pathways participated in the regulation of various cellular processes in CSCs. In the present study, we observed the translocation of CD44 from cytoplasm to nuclear in the reprogramming process of C3A cells, full-length CD44 presented in the nucleus of liver iCSCs. CD44 was bound with importin β and transportin 1 in liver iCSCs. Inhibition of importin β transport leads to reduction of CD44 in the nucleus. Translocation of CD44 is also influenced by importin α. Besides, overexpression of naïve pluripotent genes, KLF2, KLF5, DNMT3L, GBX2, ZFP42, ESRRB and DPPA4 were found in liver iCSCs. Inhibition of CD44 leads to the reduction of these naïve genes. Luciferase and chromatin immunoprecipitation (ChIP) assays further identified nuclear CD44 bound to the promoter regions of naïve genes, KLF2, KLF5, and ESRRB functioned as transcriptional activators in liver iCSCs. Our present work provides new insight into the dynamic states and functions of CD44 in iCSCs.

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“…C3A-iCSCs were generated by OSKM transduction and possessed a faster proliferation rate, with PES1 up-regulation promoting proliferation Reprogramming of C3A cells was performed in preliminary work with four reprogramming factors, Oct4, Sox2, Klf4 and c-Myc (OSKM). These cells were named C3A-iCSCs and are preserved in our laboratory [25,26]. We found that the growth of C3A-iCSCs was faster compared with C3A.…”

Section: Resultsmentioning

confidence: 98%

“…Reprogramming of C3A cells was performed in preliminary work with four reprogramming factors, Oct4, Sox2, Klf4 and c‐Myc (OSKM). These cells were named C3A‐iCSCs and are preserved in our laboratory . We found that the growth of C3A‐iCSCs was faster compared with C3A.…”

Section: Resultsmentioning

confidence: 98%

PES1 is regulated by CD44 in liver cancer stem cells via miR‐105‐5p

Wei

Liu

et al. 2019

FEBS Letters

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Pescadillo (PES1) is a key molecule for ribosome formation in mammalian cells. In this study, human hepatoma C3A cells were reprogrammed by four transcription factors, Oct4, Sox2, Klf4 and c‐Myc, into induced cancer stem cells, termed C3A‐induced cancer stem cells (C3A‐iCSCs). We found that PES1 was up‐regulated in C3A‐iCSCs and promoted cell proliferation. Moreover, the cancer stem cell marker CD44, which is located in the cytomembrane, translocated to the nucleus and was up‐regulated in C3A‐iCSCs. Our results suggest that CD44 has a negative effect on miR‐105‐5p. We found that PES1 is a direct target of, and was negatively regulated by, miR‐105‐5p. In summary, CD44 regulates PES1 in liver cancer stem cells via miR‐105‐5p to promote cell growth.

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MBD3 inhibits formation of liver cancer stem cells

Cited by 14 publications

References 31 publications

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

MBD3/NuRD loss participates with KDM6A program to promoteDOCK5/8expression and Rac GTPase activation in human acute myeloid leukemia

Nuclear CD44 Mediated by Importin β Participated in Naïve Genes Transcriptional Regulation in C3A-iCSCs

PES1 is regulated by CD44 in liver cancer stem cells via miR‐105‐5p

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