Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma
Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma
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DOI：
10.1172/jci98747
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发表时间：
2019-04-01
影响因子：
15.9
通讯作者：
Verma, Amit
中科院分区：
文献类型：
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作者：
Shenoy, Niraj;Bhagat, Tushar D.;Verma, Amit
尽管透明细胞肾细胞癌（ccRCC）已被证明会导致广泛的异常胞嘧啶甲基化和5-羟甲基胞嘧啶（5 hmC）丢失，但这种表观遗传异常的预后影响和治疗靶向尚未得到充分探讨。对576例原发性ccRCC样本的分析表明，5 hmC的缺失与侵袭性临床病理特征密切相关，并且是独立的不良预后因素。5 hmC的丢失也预示着非转移性疾病切除后无进展生存率的降低。ccRCC中5 hmC的缺失不是由于10个11易位（泰特）酶的突变或转录失活，而是由于L2-羟基戊二酸（L2 HG）脱氢酶（L2 HGDH）的缺失和低表达而导致L2 HG的过表达而使其功能失活。抗坏血酸（AA）通过泰特激活降低甲基化并恢复全基因组5 hmC水平。在AA存在下，重组泰特-2蛋白的荧光猝灭不受L2 HG的影响。药理学AA治疗导致ccRCC体外生长减少，体内肿瘤生长减少，肿瘤内5 hmC增加。这些数据表明，降低的5 hmC与ccRCC中的存活率降低相关，并为探索高剂量AA在ccRCC中的治疗潜力提供了临床前依据。
Although clear cell renal cell carcinoma (ccRCC) has been shown to result in widespread aberrant cytosine methylation and loss of 5-hydroxymethylcytosine (5hmC), the prognostic impact and therapeutic targeting of this epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was strongly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression-free survival after resection of nonmetastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of ten eleven translocation (TET) enzymes, but to their functional inactivation by L-2-hydroxyglutarate (L2HG), which was overexpressed due to the deletion and underexpression of L2HG dehydrogenase (L2HGDH). Ascorbic acid (AA) reduced methylation and restored genome-wide 5hmC levels via TET activation. Fluorescence quenching of the recombinant TET-2 protein was unaffected by L2HG in the presence of AA. Pharmacologic AA treatment led to reduced growth of ccRCC in vitro and reduced tumor growth in vivo, with increased intratumoral 5hmC. These data demonstrate that reduced 5hmC is associated with reduced survival in ccRCC and provide a preclinical rationale for exploring the therapeutic potential of high-dose AA in ccRCC.