Abstract
Cln Three Requiring 9 (CTR9), a scaffold protein of the polymerase-associated factor-1 (PAF1) complex (PAF1c), is primarily localized in the nucleus of cells. Recent studies show that CTR9 plays essential roles in the development of various human cancers and their occurrence; however, its regulatory roles and precise mechanisms in hepatocellular carcinoma (HCC) remain unclear. In this study, we investigated the roles of CTR9 using in vitro assays and a xenograft mouse model. We found that CTR9 protein is upregulated in tumor tissues from HCC patients. Knockdown of CTR9 substantially reduced HCC cell proliferation, invasion, and migration, whereas its overexpression promoted these activities. In addition, in vitro results revealed that CTR9 silencing dramatically increased cell cycle regulators, p21 and p27, but markedly decreased matrix metalloproteinases, MMP2 and MMP9, with these outcomes reversed upon CTR9 overexpression. Furthermore, the underlying molecular mechanism suggests that CTR9 promoted the oncogene paternally expressed gene 10 (PEG10) transcription via its promoter region. Finally, the oncogenic roles of CTR9 were confirmed in a xenograft mouse model. This study confirms that CTR9, an oncoprotein that promotes HCC cell proliferation, invasion, and migration, increases tumor growth in a xenograft mouse model. CTR9 could be a novel therapeutic target. Further investigation is warranted to verify CTR9 potential in novel therapies for HCC.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7–33.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.
Chok K. Management of recurrent hepatocellular carcinoma after liver transplant. World J Hepatol. 2015;7:1142–8.
Shi X, Chang M, Wolf AJ, Chang CH, Frazer-Abel AA, Wade PA, et al. Cdc73p and Paf1p are found in a novel RNA polymerase II-containing complex distinct from the Srbp-containing holoenzyme. Mol Cell Biol. 1997;17:1160–9.
Squazzo SL, Costa PJ, Lindstrom DL, Kumer KE, Simic R, Jennings JL, et al. The Paf1 complex physically and functionally associates with transcription elongation factors in vivo. EMBO J. 2002;21:1764–74.
Mueller CL, Jaehning JA. Ctr9, Rtf1, and Leo1 are components of the Paf1/RNA polymerase II complex. Mol Cell Biol. 2002;22:1971–80.
Zhang K, Haversat JM, Mager J. CTR9/PAF1c regulates molecular lineage identity, histone H3K36 trimethylation and genomic imprinting during preimplantation development. Dev Biol. 2013;383:15–27.
De Gois S, Slama P, Pietrancosta N, Erdozain AM, Louis F, Bouvrais-Veret C. et al. Ctr9, a protein in the transcription complex Paf1, regulates dopamine transporter activity at the plasma membrane. J Biol Chem. 2015;290:17848–62.
Yoo HS, Seo JH, Yoo JY. CTR9, a component of PAF complex, controls elongation block at the c-Fos locus via signal-dependent regulation of chromatin-bound NELF dissociation. PLoS One. 2013;8:e61055.
Mozdy AD, Podell ER, Cech TR. Multiple yeast genes, including Paf1 complex genes, affect telomere length via telomerase RNA abundance. Mol Cell Biol. 2008;28:4152–61.
Rodrigues J, Lydall D. Paf1 and Ctr9, core components of the PAF1 complex, maintain low levels of telomeric repeat containing RNA. Nucleic Acids Res. 2018;46:621–34.
Yoo HS, Choi Y, Ahn N, Lee S, Kim WU, Jang MS, et al. Transcriptional regulator CTR9 inhibits Th17 differentiation via repression of IL-17 expression. J Immunol. 2014;192:1440–8.
Youn MY, Yoo HS, Kim MJ, Hwang SY, Choi Y, Desiderio SV, et al. hCTR9, a component of Paf1 complex, participates in the transcription of interleukin 6-responsive genes through regulation of STAT3-DNA interactions. J Biol Chem. 2007;282:34727–34.
Lee JW, Bae E, Kwon SH, Yu MY, Cha RH, Lee H, et al. Transcriptional modulation of the T helper 17/interleukin 17 axis ameliorates renal ischemia-reperfusion injury. Nephrol Dial Transpl. 2019;34:1481–98.
Hanks S, Perdeaux ER, Seal S, Ruark E, Mahamdallie SS, Murray A, et al. Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour. Nat Commun. 2014;5:4398.
Zeng H, Xu W. Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis. Genes Dev. 2015;29:2153–67.
Li CM, Margolin AA, Salas M, Memeo L, Mansukhani M, Hibshoosh H, et al. PEG10 is a c-MYC target gene in cancer cells. Cancer Res. 2006;66:665–72.
Hishida T, Naito K, Osada S, Nishizuka M, Imagawa M. peg10, an imprinted gene, plays a crucial role in adipocyte differentiation. FEBS Lett. 2007;581:4272–8.
Peng YP, Zhu Y, Yin LD, Zhang JJ, Wei JS, Liu X, et al. PEG10 overexpression induced by E2F-1 promotes cell proliferation, migration, and invasion in pancreatic cancer. J Exp Clin Cancer Res. 2017;36:30.
Okabe H, Satoh S, Furukawa Y, Kato T, Hasegawa S, Nakajima Y, et al. Involvement of PEG10 in human hepatocellular carcinogenesis through interaction with SIAH1. Cancer Res. 2003;63:3043–8.
Deng X, Hu Y, Ding Q, Han R, Guo Q, Qin J. et al. PEG10 plays a crucial role in human lung cancer proliferation, progression, prognosis and metastasis. Oncol Rep. 2014;32:2159–67.
Ip WK, Lai PB, Wong NL, Sy SM, Beheshti B, Squire JA, et al. Identification of PEG10 as a progression related biomarker for hepatocellular carcinoma. Cancer Lett. 2007;250:284–91.
Kainz B, Shehata M, Bilban M, Kienle D, Heintel D, Krömer-Holzinger E, et al. Overexpression of the paternally expressed gene 10 (PEG10) from the imprinted locus on chromosome 7q21 in high-risk B-cell chronic lymphocytic leukemia. Int J Cancer. 2007;121:1984–93.
Xiong J, Qin J, Zheng Y, Peng X, Luo Y, Meng X. PEG10 promotes the migration of human Burkitt’s lymphoma cells by up-regulating the expression of matrix metalloproteinase-2 and −9. Clin Invest Med. 2012;35:E117–25.
Zang W, Wang T, Huang J, Li M, Wang Y, Du Y, et al. Long noncoding RNA PEG10 regulates proliferation and invasion of esophageal cancer cells. Cancer Gene Ther. 2015;22:138–44.
Li X, Xiao R, Tembo K, Hao L, Xiong M, Pan S, et al. PEG10 promotes human breast cancer cell proliferation, migration and invasion. Int J Oncol. 2016;48:1933–42.
Liu Z, Tian Z, Cao K, Zhang B, Wen Q, Zhou X, et al. TSG101 promotes the proliferation, migration and invasion of hepatocellular carcinoma cells by regulating the PEG10. J Cell Mol Med. 2019;23:70–82.
Martins AG, Pinto AT, Domingues R, Cavaco BM. Identification of a novel CTR9 germline mutation in a family with Wilms tumor. Eur J Med Genet. 2018;61:294–99.
Zeng H, Lu L, Chan NT, Horswill M, Ahlquist P, Zhong X. et al. Systematic identification of Ctr9 regulome in ERα-positive breast cancer. BMC Genom. 2016;17:902
Xu Y, Chen J, He G, Zhang Y. CTR9-mediated JAK2/STAT3 pathway promotes the proliferation, migration, and invasion of human glioma cells. J Clin Lab Anal. 2021;35:e23943.
Zhao X, Reebye V, Hitchen P, Fan J, Jiang H, Sætrom P, et al. Mechanisms involved in the activation of C/EBPα by small activating RNA in hepatocellular carcinoma. Oncogene. 2019;38:3446–57.
Ono R, Kobayashi S, Wagatsuma H, Aisaka K, Kohda T, Kaneko-Ishino T, et al. A retrotransposon-derived gene, PEG10, is a novel imprinted gene located on human chromosome 7q21. Genomics. 2001;73:232–7.
Jia HL, Ye QH, Qin LX, Budhu A, Forgues M, Chen Y, et al. Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma. Clin Cancer Res. 2007;13:1133–9.
Deng P, Zhou Y, Jiang J, Li H, Tian W, Cao Y, et al. Transcriptional elongation factor Paf1 core complex adopts a spirally wrapped solenoidal topology. Proc Natl Acad Sci USA. 2018;115:9998–10003.
Allan RK, Ratajczak T. Versatile TPR domains accommodate different modes of target protein recognition and function. Cell Stress Chaperones. 2011;16:353–67.
Acknowledgements
This research was supported by the Jiangsu Provincial Commission of Health and Family Planning [H2018037 and BJ18010], the Basic Research Program of Jiangsu Province [BK20191153], the Xuzhou Institute of Technology [KC20091 and KC19035], the National Natural Science Foundation of China [81874081], the Jiangsu Provincial Qing Lan Project and Jiangsu Provincial Medical Youth Talent [QNRC2016784], the Young Science and Technology Innovation Team of Xuzhou Medical University Key Research and Development Plan of Jiangsu Province [TD202006], and the Jiangsu Postgraduate Research Innovation Program [KYCX19_2237].
Author information
Authors and Affiliations
Contributions
BZ, ZYL, RW, CMZ, KC, WGS, ZL, MJ, and ZLT conducted the experiments; BZ, ZYL, GS, HLS, and RHW designed the experiments; ZYL and RW wrote the manuscript; BZ, GS, HLS, and RHW revised the manuscript. All authors participated in the study’s design, analysis of the data, interpretation of the findings, and review of the manuscript and agreed to the publication of the final version.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Supplementary information
Rights and permissions
About this article
Cite this article
Zhang, B., Liu, Zy., Wu, R. et al. Transcriptional regulator CTR9 promotes hepatocellular carcinoma progression and metastasis via increasing PEG10 transcriptional activity. Acta Pharmacol Sin 43, 2109–2118 (2022). https://doi.org/10.1038/s41401-021-00812-3
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41401-021-00812-3
Keywords
This article is cited by
-
Deficiency of SIAH1 promotes the formation of filopodia by increasing the accumulation of FASN in liver cancer
Cell Death & Disease (2024)
-
Molecular mechanisms behind ROS regulation in cancer: A balancing act between augmented tumorigenesis and cell apoptosis
Archives of Toxicology (2023)
