LncRNA SLC26A4-AS1 Suppresses the MRN Complex-mediated DNA Repair Signaling and Thyroid Cancer Metastasis by Destabilizing DDX5

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2020 Sep 17

PMID 32939012

Citations 40

Authors

Jupeng Yuan

Yemei Song

Wenting Pan

Yankang Li

Yeyang Xu

Mengyu Xie

Yue Shen

Nasha Zhang

Jiandong Liu

Hui Hua

Bowen Wang

Changming An

Ming Yang

Affiliations

Soon will be listed here.

Abstract

Lymph node metastasis is the major adverse feature for recurrence and death of thyroid cancer patients. To identify lncRNAs involved in thyroid cancer metastasis, we systemically screened differentially expressed lncRNAs in lymph node metastasis, thyroid cancer, and normal tissues via RNAseq. We found that lncRNA SLC26A4-AS1 was continuously, significantly down-regulated in normal tissues, thyroid cancer, and lymph node metastasis specimens. Low SLC26A4-AS1 levels in tissues were significantly associated with poor prognosis of thyroid cancer patients. LncRNA SLC26A4-AS1 markedly inhibited migration, invasion, and metastasis capability of cancer cells in vitro and in vivo. Intriguingly, SLC26A4-AS1 could simultaneously interact with DDX5 and the E3 ligase TRIM25, which promoting DDX5 degradation through the ubiquitin-proteasome pathway. In particular, SLC26A4-AS1 inhibited expression of multiple DNA double-strand breaks (DSBs) repair genes, especially genes coding proteins in the MRE11/RAS50/NBS1 (MRN) complex. Enhanced interaction between DDX5 and transcriptional factor E2F1 due to silencing of SLC26A4-AS1 promoted binding of the DDX5-E2F1 complex at promoters of the MRN genes and, thus, stimulate the MRN/ATM dependent DSB signaling and thyroid cancer metastasis. Our study uncovered new insights into the biology driving thyroid cancer metastasis and highlights potentials of lncRNAs as future therapeutic targets again cancer metastasis.

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References

Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6):394-424. DOI: 10.3322/caac.21492. View

Kim S, Kim B, Pyo J, Hong S, Chang H, Park C . Macrometastasis in Papillary Thyroid Cancer Patients is Associated with Higher Recurrence in Lateral Neck Nodes. World J Surg. 2017; 42(1):123-129. DOI: 10.1007/s00268-017-4158-5. View

Gudmundsson J, Sulem P, Gudbjartsson D, Jonasson J, Sigurdsson A, Bergthorsson J . Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nat Genet. 2009; 41(4):460-4. PMC: 3664837. DOI: 10.1038/ng.339. View

Gudmundsson J, Sulem P, Gudbjartsson D, Jonasson J, Masson G, He H . Discovery of common variants associated with low TSH levels and thyroid cancer risk. Nat Genet. 2012; 44(3):319-22. PMC: 3655412. DOI: 10.1038/ng.1046. View

Figlioli G, Kohler A, Chen B, Elisei R, Romei C, Cipollini M . Novel genome-wide association study-based candidate loci for differentiated thyroid cancer risk. J Clin Endocrinol Metab. 2014; 99(10):E2084-92. DOI: 10.1210/jc.2014-1734. View

He H, Li W, Liyanarachchi S, Srinivas M, Wang Y, Akagi K . Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer. Proc Natl Acad Sci U S A. 2015; 112(19):6128-33. PMC: 4434723. DOI: 10.1073/pnas.1506255112. View

Swierniak M, Wojcicka A, Czetwertynska M, Dlugosinska J, Stachlewska E, Gierlikowski W . Association between GWAS-Derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer. Clin Cancer Res. 2015; 22(5):1111-9. DOI: 10.1158/1078-0432.CCR-15-1746. View

Gudmundsson J, Thorleifsson G, Sigurdsson J, Stefansdottir L, Jonasson J, Gudjonsson S . A genome-wide association study yields five novel thyroid cancer risk loci. Nat Commun. 2017; 8:14517. PMC: 5316879. DOI: 10.1038/ncomms14517. View

Son H, Hwangbo Y, Yoo S, Im S, Yang S, Kwak S . Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer. Nat Commun. 2017; 8:15966. PMC: 5511346. DOI: 10.1038/ncomms15966. View

10.

Hwangbo Y, Lee E, Son H, Im S, Kwak S, Yoon J . Genome-Wide Association Study Reveals Distinct Genetic Susceptibility of Thyroid Nodules From Thyroid Cancer. J Clin Endocrinol Metab. 2018; 103(12):4384-4394. DOI: 10.1210/jc.2017-02439. View

11.

Jendrzejewski J, Liyanarachchi S, Eiterman A, Thomas A, He H, Nagy R . Fine mapping of 14q13 reveals novel variants associated with different histological subtypes of papillary thyroid carcinoma. Int J Cancer. 2018; 144(3):503-512. PMC: 6294684. DOI: 10.1002/ijc.31933. View

12.

Liyanarachchi S, Gudmundsson J, Ferkingstad E, He H, Jonasson J, Tragante V . Assessing thyroid cancer risk using polygenic risk scores. Proc Natl Acad Sci U S A. 2020; 117(11):5997-6002. PMC: 7084156. DOI: 10.1073/pnas.1919976117. View

13.

Jendrzejewski J, He H, Radomska H, Li W, Tomsic J, Liyanarachchi S . The polymorphism rs944289 predisposes to papillary thyroid carcinoma through a large intergenic noncoding RNA gene of tumor suppressor type. Proc Natl Acad Sci U S A. 2012; 109(22):8646-51. PMC: 3365219. DOI: 10.1073/pnas.1205654109. View

14.

He H, Li W, Liyanarachchi S, Jendrzejewski J, Srinivas M, Davuluri R . Genetic predisposition to papillary thyroid carcinoma: involvement of FOXE1, TSHR, and a novel lincRNA gene, PTCSC2. J Clin Endocrinol Metab. 2014; 100(1):E164-72. PMC: 4283026. DOI: 10.1210/jc.2014-2147. View

15.

Zhu H, Lv Z, An C, Shi M, Pan W, Zhou L . Onco-lncRNA HOTAIR and its functional genetic variants in papillary thyroid carcinoma. Sci Rep. 2016; 6:31969. PMC: 4994070. DOI: 10.1038/srep31969. View

16.

Wang Y, He H, Li W, Phay J, Shen R, Yu L . MYH9 binds to lncRNA gene PTCSC2 and regulates FOXE1 in the 9q22 thyroid cancer risk locus. Proc Natl Acad Sci U S A. 2017; 114(3):474-479. PMC: 5255605. DOI: 10.1073/pnas.1619917114. View

17.

Knoll M, Lodish H, Sun L . Long non-coding RNAs as regulators of the endocrine system. Nat Rev Endocrinol. 2015; 11(3):151-60. PMC: 4376378. DOI: 10.1038/nrendo.2014.229. View

18.

Pan W, Zhang N, Liu W, Liu J, Zhou L, Liu Y . The long noncoding RNA suppresses hepatocarcinogenesis by epigenetically activating the tumor suppressor . J Biol Chem. 2018; 293(44):17154-17165. PMC: 6222094. DOI: 10.1074/jbc.RA118.003055. View

19.

Ren Y, Shang J, Li J, Liu W, Zhang Z, Yuan J . The long noncoding RNA links the microRNA miR-215 to oncogene CRKL-mediated signaling in hepatocellular carcinoma. J Biol Chem. 2017; 292(43):17939-17949. PMC: 5663891. DOI: 10.1074/jbc.M116.773978. View

20.

Huarte M . The emerging role of lncRNAs in cancer. Nat Med. 2015; 21(11):1253-61. DOI: 10.1038/nm.3981. View