ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation.
ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation.
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ABHD5 通过抑制 YAP 甲基化来抑制 YAP 诱导的 c-Met 过表达和结肠癌细胞干性
DOI：
10.1038/s41467-021-26967-5
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发表时间：
2021-11-18
影响因子：
16.6
通讯作者：
Ou J
中科院分区：
文献类型：
--
作者：
Gu Y;Chen Y;Wei L;Wu S;Shen K;Liu C;Dong Y;Zhao Y;Zhang Y;Zhang C;Zheng W;He J;Wang Y;Li Y;Zhao X;Wang H;Tan J;Wang L;Zhou Q;Xie G;Liang H;Ou J
癌症干性是结直肠癌（CRC）发生和进展的主要来源。c-Met对CRC的干性有重要作用，但c-Met如何在CRC中被激活仍然是一个谜。我们以前确定的脂肪分解因子ABHD 5作为一个重要的肿瘤抑制基因在CRC。在这里，我们表明ABHD 5的缺失促进了c-Met的激活，从而以非经典的方式维持CRC的干性。从机制上讲，我们证明ABHD 5在细胞质中与SET 1A甲基转移酶复合物DPY 30的核心亚基相互作用，从而抑制DPY 30的核转位和SET 1A的活性。在缺乏ABHD 5的情况下，DPY 30易位至细胞核并支持SET 1A介导的雅普和组蛋白H3的甲基化，其在细胞核中隔离雅普并增加染色质可及性以协同促进YAP诱导的c-Met转录，从而促进CRC细胞的干细胞性。这项研究揭示了ABHD 5在调节组蛋白/非组蛋白甲基化和CRC干性中的新作用。这项研究揭示了ABHD 5通过控制雅普甲基化和核定位在调节结肠癌干细胞中未被认识到的作用，进一步解释了ABHD 5作为结肠癌肿瘤抑制基因的分子机制。
Cancer stemness represents a major source of development and progression of colorectal cancer (CRC). c-Met critically contributes to CRC stemness, but how c-Met is activated in CRC remains elusive. We previously identified the lipolytic factor ABHD5 as an important tumour suppressor gene in CRC. Here, we show that loss of ABHD5 promotes c-Met activation to sustain CRC stemness in a non-canonical manner. Mechanistically, we demonstrate that ABHD5 interacts in the cytoplasm with the core subunit of the SET1A methyltransferase complex, DPY30, thereby inhibiting the nuclear translocation of DPY30 and activity of SET1A. In the absence of ABHD5, DPY30 translocates to the nucleus and supports SET1A-mediated methylation of YAP and histone H3, which sequesters YAP in the nucleus and increases chromatin accessibility to synergistically promote YAP-induced transcription of c-Met, thus promoting the stemness of CRC cells. This study reveals a novel role of ABHD5 in regulating histone/non-histone methylation and CRC stemness. This study reveals an unrecognized role of ABHD5 in regulating colon cancer stemness via controlling YAP methylation and nuclear localization, further explaining the molecular mechanism through which ABHD5 functions as a tumour suppressor gene in colon cancer.
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影响因子：
23.9
作者：
Li, Qi;Sun, Yang;Mao, Junhao
通讯作者：
Mao, Junhao
影响因子：
64.8
作者：
Gregorieff, Alex;Liu, Yu;Wrana, Jeffrey L.
通讯作者：
Wrana, Jeffrey L.
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.
影响因子：
56.9
作者：
Haemmerle, G;Lass, A;Zechner, R
通讯作者：
Zechner, R
影响因子：
64.5
作者：
Azzolin, Luca;Panciera, Tito;Piccolo, Stefano
通讯作者：
Piccolo, Stefano