Theranostics 2019; 9(3):811-828. doi:10.7150/thno.29271 This issue Cite

Research Paper

RACK1 Promotes Self-Renewal and Chemoresistance of Cancer Stem Cells in Human Hepatocellular Carcinoma through Stabilizing Nanog

Junxia Cao1,*, Min Zhao1,2,*, Jian Liu1,2, Xueying Zhang1, Yujun Pei1, Jingyang Wang1, Xiao Yang3, Beifen Shen1,2, Jiyan Zhang1,2,✉

1. Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, China
2. Beijing Institute of Brain Sciences, 27 Taiping Road, Beijing 100850, China
3. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China
*These authors contributed equally to this work.

Citation:
Cao J, Zhao M, Liu J, Zhang X, Pei Y, Wang J, Yang X, Shen B, Zhang J. RACK1 Promotes Self-Renewal and Chemoresistance of Cancer Stem Cells in Human Hepatocellular Carcinoma through Stabilizing Nanog. Theranostics 2019; 9(3):811-828. doi:10.7150/thno.29271. https://www.thno.org/v09p0811.htm
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Abstract

Graphic abstract

Targeting cancer stem cells (CSCs) has been proposed as a new strategy to eradicate malignancies, including hepatocellular carcinoma (HCC). However, the mechanisms by which CSCs sustain their self-renewal and chemoresistance remain elusive. Nanog is a master transcriptional regulator of stemness, especially in CSCs. Its expression is tightly regulated by the ubiquitin-proteasome system in embryonic stem cells (ESCs). Whether the suppression of Nanog ubiquitination contributes to its over-expression in CSCs has not been explored. In addition, the role of receptor for activated C kinase 1 (RACK1), an adaptor protein implicated in HCC growth, in liver CSC-like traits remains to be determined.

Methods: In vitro and in vivo assays were performed to investigate the role of RACK1 in liver CSC-like phenotype and murine ESC function. How RACK1 regulates Nanog expression was explored by immunoblotting and immunohistochemistry. The interaction of RACK1 with Nanog and the consequent effects on Nanog ubiquitination and stemness were then analyzed.

Results: RACK1 promotes self-renewal and chemoresistance of human liver CSCs and maintains murine ESC function. Consistently, RACK1 enhances the expression of Nanog in human HCC cells and murine ESCs. The protein levels of RACK1 in clinical HCC tissues positively correlate with those of Nanog. Further exploration indicates that RACK1 directly binds to Nanog, which prevents its recruitment of E3 ubiquitin ligase FBXW8 and ubiquitin-dependent degradation. The interaction with Nanog is essential for RACK1 to promote stemness.

Conclusions: Our data provide novel insights into the regulation of Nanog protein levels, as well the key role of RACK1 to enhance self-renewal and chemoresistance of CSCs in human HCC.

Keywords: Nanog, RACK1, CSCs, ESCs, ubiquitination


Citation styles

APA
Cao, J., Zhao, M., Liu, J., Zhang, X., Pei, Y., Wang, J., Yang, X., Shen, B., Zhang, J. (2019). RACK1 Promotes Self-Renewal and Chemoresistance of Cancer Stem Cells in Human Hepatocellular Carcinoma through Stabilizing Nanog. Theranostics, 9(3), 811-828. https://doi.org/10.7150/thno.29271.

ACS
Cao, J.; Zhao, M.; Liu, J.; Zhang, X.; Pei, Y.; Wang, J.; Yang, X.; Shen, B.; Zhang, J. RACK1 Promotes Self-Renewal and Chemoresistance of Cancer Stem Cells in Human Hepatocellular Carcinoma through Stabilizing Nanog. Theranostics 2019, 9 (3), 811-828. DOI: 10.7150/thno.29271.

NLM
Cao J, Zhao M, Liu J, Zhang X, Pei Y, Wang J, Yang X, Shen B, Zhang J. RACK1 Promotes Self-Renewal and Chemoresistance of Cancer Stem Cells in Human Hepatocellular Carcinoma through Stabilizing Nanog. Theranostics 2019; 9(3):811-828. doi:10.7150/thno.29271. https://www.thno.org/v09p0811.htm

CSE
Cao J, Zhao M, Liu J, Zhang X, Pei Y, Wang J, Yang X, Shen B, Zhang J. 2019. RACK1 Promotes Self-Renewal and Chemoresistance of Cancer Stem Cells in Human Hepatocellular Carcinoma through Stabilizing Nanog. Theranostics. 9(3):811-828.

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