Loss of nuclear localization of TET2 in colorectal cancer
- Yuji Huang†1, 2,
- Guanghui Wang†1, 2,
- Zhonglin Liang1, 2,
- Yili Yang1, 2,
- Long Cui1, 2 and
- Chen-Ying Liu1, 2Email author
© Huang et al. 2016
Received: 12 October 2015
Accepted: 17 January 2016
Published: 26 January 2016
5-Hydroxymethylcytosine (5hmC) is lost in multiple human cancers, including colorectal cancer (CRC). Decreased ten-eleven translocation 1 (TET1) messenger RNA (mRNA), but not other two TET family members, has been observed in the colorectal cancer and is crucial for colorectal cancer initiation. Here, we show that nuclear localization of TET2 was lost in a significant portion of CRC tissues, in association with metastasis. In CRC cells, nuclear expression of TET2 were absent but not TET3. Nuclear export inhibitor can increase the 5hmC level in CRC cells, probably through regulating TET2. Our results indicate a new mechanism of TET2 dysregulation in colorectal cancer.
KeywordsTET2 Colorectal cancer 5hmC DNA methylation Nuclear localization
5-Hydroxymethylcytosine (5hmC) is lost in multiple human cancers, including colorectal cancer. Inactivation of the ten-eleven translocation (TET) family members, the DNA hydroxylases catalyze 5mC into 5hmC, was closely related to the cancer initiation and progression. Recently, F Neri et al. reported the downregulation of TET1 messenger RNA (mRNA) expression level, but not other two TET family members, in colon cancer and showed that decreased TET1 mRNA was crucial for colon cancer initiation and TET1 functioned as a tumor suppressor by inhibiting the WNT pathway . However, another group observed the decreased mRNA level of all TET family members in the colorectal cancer . These contradictory findings could be due to the interfering by the stromal and infiltrating immune cells in the tumor tissues, the unstable mRNA in the tissue samples, and the RNA degradation during the RNA extraction. Besides, it was reported that the reduced levels of 5hmC in colorectal cancers is not correlated with TET mRNA levels , which indicates that dysregulation of TET protein could play a vital role in colorectal cancer. Thus, we analyzed both the mRNA and protein level of the TET family members in our colorectal cancer specimens.
DNA methylation is a therapeutic target for cancer treatment . DNA hypermethylation occurs to the promoter of tumor suppressor genes, resulting in decreased expression of the tumor suppressor and cancer initiation and progression . Inhibitors of DNA methyltransferases like 5-azacytidine and 5-aza-2′-deoxycytidine have been shown the efficacy in the treatment of multiple cancers to induce the expression of the tumor suppressor genes . DNA hypermethylation of tumor suppressor genes could be due to the loss of active DNA demethylation which is consistent with global loss of 5hmC level in cancers [4, 7]. Thus, re-activation of the active DNA demethylation process could also lead to the re-expression of the tumor suppressor genes. The nuclear export inhibitors is also a promising cancer treatment drugs which have been shown to inhibit nuclear export of tumor suppressors like TP53 . Here, we showed that LMB treatment can increase the global level of 5hmC probably through regulating TET2 in the CRC cell lines, which could promote the active demethylation and expression of tumor suppressor genes. Our results provided a novel mechanism that nuclear export inhibitor functioning through restoring the 5hmC level and potential expression of tumor suppressor genes which need to be further studied in the future.
Several mechanisms have been reported for the dysregulation of TET2 in cancers, including mutation of TET2 gene  and decreasing TET2 mRNA expression level [10, 11]. Nuclear exclusion of TET1 protein was found in the IDH1 wild-type gliomas . Nuclear translocation of TET2 was first reported in the B cells ; furthermore, our results demonstrated that nuclear translocation of TET2 was also dysregulated in colorectal cancer, probably through the post-translational modification. Since TET2 needs to interact with DNA binding partners to regulate gene expression in the nucleus, loss of TET2 nuclear expression impaired TET2’s function. Thus, TET2 could also be a tumor suppressor in colorectal cancer, and the tumor suppressor function of both TET1 and TET2 was impaired in colorectal cancer through different mechanism.
This work was supported by the National Natural Science Foundation of China (Grant No. 81372636, No. 81302089, No. 81572378, No. 81502020), the National High Technology Research and Development Program of China (863 Program) (Grant No. 2014AA020801), and the Shanghai Excellent Young Teachers Program (Grant No. ZZjdyx13074).
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Neri F, Dettori D, Incarnato D, Krepelova A, Rapelli S, Maldotti M, et al. TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway. Oncogene. 2015;34(32):4168–76.View ArticlePubMedGoogle Scholar
- Rawluszko-Wieczorek AA, Siera A, Horbacka K, Horst N, Krokowicz P, Jagodzinski PP. Clinical significance of DNA methylation mRNA levels of TET family members in colorectal cancer. J Cancer Res Clin Oncol. 2015;141(8):1379–92.PubMed CentralView ArticlePubMedGoogle Scholar
- Uribe-Lewis S, Stark R, Carroll T, Dunning MJ, Bachman M, Ito Y, et al. 5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer. Genome Biol. 2015;16:69.PubMed CentralView ArticlePubMedGoogle Scholar
- Kudo Y, Tateishi K, Yamamoto K, Yamamoto S, Asaoka Y, Ijichi H, et al. Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation. Cancer Sci. 2012;103(4):670–6.View ArticlePubMedGoogle Scholar
- Szyf M. Epigenetics, DNA methylation, and chromatin modifying drugs. Annu Rev Pharmacol Toxicol. 2009;49:243–63.View ArticlePubMedGoogle Scholar
- Heyn H, Esteller M. DNA methylation profiling in the clinic: applications and challenges. Nat Rev Genet. 2012;13(10):679–92.View ArticlePubMedGoogle Scholar
- Jin SG, Jiang Y, Qiu R, Rauch TA, Wang Y, Schackert G, et al. 5-Hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res. 2011;71(24):7360–5.PubMed CentralView ArticlePubMedGoogle Scholar
- Mutka SC, Yang WQ, Dong SD, Ward SL, Craig DA, Timmermans PB, et al. Identification of nuclear export inhibitors with potent anticancer activity in vivo. Cancer Res. 2009;69(2):510–7.PubMed CentralView ArticlePubMedGoogle Scholar
- Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468(7325):839–43.PubMed CentralView ArticlePubMedGoogle Scholar
- Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, et al. Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene. 2013;32(5):663–9.PubMed CentralView ArticlePubMedGoogle Scholar
- Sajadian SO, Ehnert S, Vakilian H, Koutsouraki E, Damm G, Seehofer D, et al. Induction of active demethylation and 5hmC formation by 5-azacytidine is TET2 dependent and suggests new treatment strategies against hepatocellular carcinoma. Clin Epigenetics. 2015;7(1):98.PubMed CentralView ArticlePubMedGoogle Scholar
- Muller T, Gessi M, Waha A, Isselstein LJ, Luxen D, Freihoff D, et al. Nuclear exclusion of TET1 is associated with loss of 5-hydroxymethylcytosine in IDH1 wild-type gliomas. Am J Pathol. 2012;181(2):675–83.View ArticlePubMedGoogle Scholar
- Di Stefano B, Sardina JL, van Oevelen C, Collombet S, Kallin EM, Vicent GP, et al. C/EBPalpha poises B cells for rapid reprogramming into induced pluripotent stem cells. Nature. 2014;506(7487):235–9.View ArticlePubMedGoogle Scholar