TET1-Mediated Hydroxymethylation Facilitates Hypoxic Gene Induction in Neuroblastoma

Mariani, Christopher J.; Vasanthakumar, Aparna; Madžo, Jozef; Yesilkanal, Ali E.; Bhagat, Tushar D.; Yu, Yiting; Bhattacharyya, Sanchari; Wenger, Roland H.; Cohn, Susan L.; Nanduri, Jayasri; Verma, Amit; Prabhakar, Nanduri R.; Godley, Lucy A.

doi:10.1016/j.celrep.2014.04.040

Cited by 153 publications

(157 citation statements)

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“…Finally, it should be noted that, in addition to activating transcription of the RNA demethylase ALKBH5, HIFs also regulate the expression of two other O 2 -dependent dioxygenases that play key roles in breast cancer metastasis and stem cell maintenance (43,44): JMJD2C, which mediates demethylation of histones (45), and TET1, which mediates hydroxymethylation of DNA (46). It is interesting that, in the absence of HIFs, the activity of these dioxygenases should decline under hypoxic conditions as a result of reduced substrate (i.e., O 2 ) availability.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

Zhang

Samanta

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

870

818

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N 6 -methyladenosine (m 6 A) modification of mRNA plays a role in regulating embryonic stem cell pluripotency. However, the physiological signals that determine the balance between methylation and demethylation have not been described, nor have studies addressed the role of m 6 A in cancer stem cells. We report that exposure of breast cancer cells to hypoxia stimulated hypoxiainducible factor (HIF)-1α-and HIF-2α-dependent expression of AlkB homolog 5 (ALKBH5), an m 6 A demethylase, which demethylated NANOG mRNA, which encodes a pluripotency factor, at an m 6 A residue in the 3′-UTR. Increased NANOG mRNA and protein expression, and the breast cancer stem cell (BCSC) phenotype, were induced by hypoxia in an HIF-and ALKBH5-dependent manner. Insertion of the NANOG 3′-UTR into a luciferase reporter gene led to regulation of luciferase activity by O 2 , HIFs, and ALKBH5, which was lost upon mutation of the methylated residue. ALKBH5 overexpression decreased NANOG mRNA methylation, increased NANOG levels, and increased the percentage of BCSCs, phenocopying the effect of hypoxia. Knockdown of ALKBH5 expression in MDA-MB-231 human breast cancer cells significantly reduced their capacity for tumor initiation as a result of reduced numbers of BCSCs. Thus, HIF-dependent ALKBH5 expression mediates enrichment of BCSCs in the hypoxic tumor microenvironment.hypoxia-inducible factors | metastasis | pluripotency factors | self-renewal | tumorigenesis B reast cancer has the highest incidence of all cancers affecting women (1). It is also the leading cause of cancer-related death for women worldwide (2). Although progress has been made in treating early-stage breast cancer, there is no effective strategy to prevent or treat metastasis, which is the major cause of breast cancer-related mortality (3). Within breast cancers, a small subpopulation of cells, which are designated as tumor-initiating cells or breast cancer stem cells (BCSCs), have the unique property of generating daughter BCSCs, which are capable of infinite proliferation through self-renewal, and transient amplifying cells, which are capable of a limited number of cell divisions and give rise to differentiated breast cancer cells (4, 5). Only BCSCs are capable of forming a secondary (recurrent or metastatic) tumor (5, 6). As in the case of ES cells (ESCs) (7), the BCSC phenotype is specified by the expression of core pluripotency factors, including Kruppel-like factor 4 (KLF4), Octamer-binding transcription factor 4 (OCT4), SRY-box 2 (SOX2), and NANOG (8-12). Delineation of the molecular mechanisms that regulate the BCSC phenotype is needed to better understand metastasis and design more effective therapies.Intratumoral hypoxia is a common finding in advanced cancers. The median partial pressure of oxygen (pO 2 ) within primary breast cancers is 10 mm Hg [1.4% (vol/vol) O 2 ], compared with 65 mm Hg [9.3% (vol/vol) O 2 ] in normal breast tissue (13). Hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 are heterodimeric transcriptional activators, consisting of an O 2 -regu...

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Section: Discussionmentioning

confidence: 99%

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

Zhang

Samanta

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

870

818

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“…The JHDMs cause genome-wide increases or decreases in histone methylation (Krieg et al, 2010;Kaelin and McKnight, 2013). TETs generate 5-hydroxymethylcytosine, which serves as an intermediate of DNA demethylation (Kaelin and McKnight, 2013;Mariani et al, 2014). Both of them play crucial roles in epigenetic gene regulation.…”

Section: Discussionmentioning

confidence: 99%

Critical role of TRPC6 in maintaining the stability of HIF-1α in glioma cells under hypoxia

Wang

et al. 2015

Journal of Cell Science

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Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor responsible for the expression of a broad range of genes that facilitate acclimatization to hypoxia. Its stability is predominantly controlled by rapid hydroxylation of two proline residues in its α-subunit. However, how the rapid hydroxylation of HIF-1α is regulated is not fully understood. Here, we report that transient receptor potential canonical (TRPC) 6 channels control hydroxylation and stability of HIF-1α in human glioma cells under hypoxia. TRPC6 was rapidly activated by IGF-1R-PLCγ-IP 3 R pathway upon hypoxia. Inhibition of TRPC6 enhanced the levels of α-ketoglutarate and promoted hydroxylation of HIF-1α to suppress HIF-1α accumulation without affecting its transcription or translation. Dimethyloxalylglycine N-(methoxyoxoacetyl)-glycine methyl ester (DMOG), an analog of α-ketoglutarate, reversed the inhibition of HIF-1α accumulation. Moreover, TRPC6 regulated GLUT1 (also known as SLC2A1) expression in a manner that was dependent on HIF-1α accumulation to affect glucose uptake during hypoxia. Our results suggest that TRPC6 regulates metabolism to affect HIF-1α stability and consequent glucose metabolism in human glioma cells under hypoxia.

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“…A subsequent decarboxylation of 5-caC, by etiher a theymine-DNA glycosylase or other DNA repair enzymes, could then lead to eventual DNA demethylation and promote genes expression (Yang et al, 2013;Mariani et al, 2014). There are three TET genes in mammalian cells: TET1, TET2 and TET3 (Pastor et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Hypermethylation of TET1 Promoter Is a New Diagnosic Marker for Breast Cancer Metastasis

Sang

Cheng²,

Tang³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Breast cancer metastasis is a major cause of cancer-related death in women. However, markers for diagnosis of breast cancer metastasis are rare. Here, we reported that TET1, a tumor suppressor gene, was downregulated and hypermethylated in highly metastatic breast cancer cell lines. Moreover, silencing of TET1 in breast cancer cells increased the migration and spreading of breast cancer cells. In breast cancer clinical samples, TET1 expression was reduced in LN metastases compared with primary tissues. Besides, the methylation level of the TET1 promoter was increased significantly in LN metastases. Taken together, these findings indicate that promoter hypermethylation may contribute to the downregulation of TET1 and could be used as a promising marker for diagnosis in patients with breast cancer metastasis.

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TET1-Mediated Hydroxymethylation Facilitates Hypoxic Gene Induction in Neuroblastoma

Cited by 153 publications

References 50 publications

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

Critical role of TRPC6 in maintaining the stability of HIF-1α in glioma cells under hypoxia

Hypermethylation of TET1 Promoter Is a New Diagnosic Marker for Breast Cancer Metastasis

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TET1-Mediated Hydroxymethylation Facilitates Hypoxic Gene Induction in Neuroblastoma

Cited by 153 publications

References 50 publications

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m 6 A-demethylation of NANOG mRNA

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m 6 A-demethylation of NANOG mRNA

Critical role of TRPC6 in maintaining the stability of HIF-1α in glioma cells under hypoxia

Hypermethylation of TET1 Promoter Is a New Diagnosic Marker for Breast Cancer Metastasis

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Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m ⁶ A-demethylation of NANOG mRNA