The m(6)A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function.
The m(6)A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function.
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m(6)A reader YTHDC2 通过抑制 SLC7A11 依赖性抗氧化功能来抑制肺腺癌肿瘤发生
DOI：
10.1016/j.redox.2020.101801
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发表时间：
2021-01
期刊：
影响因子：
11.4
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Ma L;Chen T;Zhang X;Miao Y;Tian X;Yu K;Xu X;Niu Y;Guo S;Zhang C;Qiu S;Qiao Y;Fang W;Du L;Yu Y;Wang J
N6-甲基腺苷（m6 A）RNA甲基化的生物学功能主要取决于读者;然而，其在肺肿瘤发生中的作用仍不清楚。在这里，我们已经证明了m6 A阅读器YT 521-含B同源结构域2（YTHDC 2）在肺腺癌（LUAD）中经常受到抑制。YTHDC 2的下调与LUAD的不良临床结局相关。YTHDC 2在自发LUAD小鼠模型中降低肿瘤发生。此外，YTHDC 2在人LUAD细胞中表现出抗肿瘤活性。从机制上讲，YTHDC 2通过其m6 A识别YTH结构域抑制胱氨酸摄取并阻断下游抗氧化程序。胱氨酸下游抗氧化剂对肺YTHDC 2过表达小鼠的给药挽救了肺肿瘤发生。此外，溶质载体7A 11（SLC 7A 11），系统XC-的催化亚基，被确定为YTHDC 2的直接目标。YTHDC 2以m6 A依赖的方式使SLC 7A 11 mRNA不稳定，因为YTHDC 2优先结合m6 A修饰的SLC 7A 11 mRNA，然后促进其衰变。临床上，大部分腺泡LUAD亚型病例同时表现出YTHDC 2下调和SLC 7A 11升高。从腺泡LUAD产生的患者来源的异种移植物（PDX）小鼠模型显示出对系统XC−抑制剂的敏感性。总的来说，通过抑制YTHDC 2促进胱氨酸摄取对于LUAD肿瘤发生至关重要，阻断这一过程可能有利于未来的治疗。m6 A阅读器YTHDC 2在LUAD中经常被抑制，并表明预后不良。YTHDC 2通过其m6 A阅读结构域抑制XC−系统的抗氧化功能。编码SLC 7A 11的mRNA是YTHDC 2的直接靶标。YTHDC 2优先加速m6 A-甲基化的SLC 7A 11 mRNA的衰变。具有YTHDC 2抑制的LUAD对系统XC−抑制剂敏感。
The biological functions of N6-methyladenosine (m6A) RNA methylation are mainly dependent on the reader; however, its role in lung tumorigenesis remains unclear. Here, we have demonstrated that the m6A reader YT521-B homology domain containing 2 (YTHDC2) is frequently suppressed in lung adenocarcinoma (LUAD). Downregulation of YTHDC2 was associated with poor clinical outcome of LUAD. YTHDC2 decreased tumorigenesis in a spontaneous LUAD mouse model. Moreover, YTHDC2 exhibited antitumor activity in human LUAD cells. Mechanistically, YTHDC2, via its m6A-recognizing YTH domain, suppressed cystine uptake and blocked the downstream antioxidant program. Administration of cystine downstream antioxidants to pulmonary YTHDC2-overexpressing mice rescued lung tumorigenesis. Furthermore, solute carrier 7A11 (SLC7A11), the catalytic subunit of system XC−, was identified to be the direct target of YTHDC2. YTHDC2 destabilized SLC7A11 mRNA in an m6A-dependent manner because YTHDC2 preferentially bound to m6A-modified SLC7A11 mRNA and thereafter promoted its decay. Clinically, a large proportion of acinar LUAD subtype cases exhibited simultaneous YTHDC2 downregulation and SLC7A11 elevation. Patient-derived xenograft (PDX) mouse models generated from acinar LUAD showed sensitivity to system XC− inhibitors. Collectively, the promotion of cystine uptake via the suppression of YTHDC2 is critical for LUAD tumorigenesis, and blocking this process may benefit future treatment. The m6A reader YTHDC2 is frequently suppressed in LUAD and indicates poor prognosis. YTHDC2 suppresses the antioxidant function of system XC− via its m6A reading domain. The mRNA encoding SLC7A11 is a direct target of YTHDC2. YTHDC2 preferentially accelerates the decay of m6A-methylated SLC7A11 mRNA. LUAD with YTHDC2 suppression is sensitive to system XC− inhibitors.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1261/rna.064238.117
发表时间：
2018-10
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Kretschmer J;Rao H;Hackert P;Sloan KE;Höbartner C;Bohnsack MT
通讯作者：
Bohnsack MT
影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
Saya, Hideyuki
影响因子：
8
作者：
Chen, R-S;Song, Y-M;Li, W.
通讯作者：
Li, W.
影响因子：
8
作者：
Chen D;Fan Z;Rauh M;Buchfelder M;Eyupoglu IY;Savaskan N
通讯作者：
Savaskan N