A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer.
A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer.
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用于 RRM2 反式激活的 MYBL2 复合物以及 MYBL2 敲低与 WEE1 抑制对结直肠癌的综合作用
DOI：
10.1038/s41419-021-03969-1
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发表时间：
2021-07-07
影响因子：
9
通讯作者：
Shao J
中科院分区：
文献类型：
--
作者：
Liu Q;Guo L;Qi H;Lou M;Wang R;Hai B;Xu K;Zhu L;Ding Y;Li C;Xie L;Shen J;Xiang X;Shao J
核糖核苷酸还原酶（RR）是一种独特的酶，用于将NDP还原为dNDP，dNDP是DNA合成的构建模块，因此对细胞增殖至关重要。泛癌症分析研究表明，RRM 2，RR的小亚基M2，在多种类型的癌症中异常过表达;然而，癌症中的潜在调控机制仍不清楚。在这项研究中，通过检索癌症组学数据库和免疫组化验证与临床样本，我们发现，MYBL 2，一个关键的致癌转录因子，表达显着上调与RRM 2在结直肠癌（CRC）。异位表达和敲低实验表明，MYBL 2是必不可少的CRC细胞增殖，DNA合成，并在RRM 2依赖的方式细胞周期的进展。MYBL 2直接与RRM 2基因启动子结合，与TAF 15和MuvB组分一起促进RRM 2基因在S期的转录。值得注意的是，MYBL 2的敲低使CRC细胞对MK-1775的治疗敏感，MK-1775是一种抑制WEE 1的临床试验药物，WEE 1参与RRM 2的降解途径。最后，小鼠异种移植实验表明，MYBL 2和WEE 1的联合抑制协同抑制CRC生长，体内全身毒性低。因此，我们提出了一种新的调节机制，RRM 2转录CRC增殖，其中MYBL 2的功能，构成一个动态的S期转录复合物后的G1/早期S期E2 Fs复合物。双重靶向RRM 2的转录和降解机器可以对RRM 2水平产生综合抑制作用，具有新的CRC治疗潜力。
Ribonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment.
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影响因子：
4.8
作者：
Lin, ZP;Belcourt, MF;Sartorelli, AC
通讯作者：
Sartorelli, AC
DOI：
10.1016/j.bbrc.2015.06.103
发表时间：
2015-08-21
影响因子：
3.1
作者：
Fang, Zejun;Gong, Chaoju;Chen, Xiang
通讯作者：
Chen, Xiang
影响因子：
4.8
作者：
Chabes, AL;Björklund, S;Thelander, L
通讯作者：
Thelander, L
影响因子：
--
作者：
Jutras, Brandon L;Verma, Ashutosh;Stevenson, Brian
通讯作者：
Stevenson, Brian
DOI：
10.1126/science.aba6794
发表时间：
2020-04-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kang G;Taguchi AT;Stubbe J;Drennan CL
通讯作者：
Drennan CL