Splicing factor USP39 promotes ovarian cancer malignancy through maintaining efficient splicing of oncogenic HMGA2.
Splicing factor USP39 promotes ovarian cancer malignancy through maintaining efficient splicing of oncogenic HMGA2.
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DOI：
10.1038/s41419-021-03581-3
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发表时间：
2021-03-17
影响因子：
9
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Wang S;Wang Z;Li J;Qin J;Song J;Li Y;Zhao L;Zhang X;Guo H;Shao C;Kong B;Liu Z
剪接因子的异常表达被发现促进肿瘤的发生和人类恶性肿瘤的发展。然而，潜在的机制和功能相关性仍然难以捉摸。我们在此发现，USP 39，剪接体的一个组成部分，在高级别浆液性卵巢癌（HGSOC）中经常过表达，并且USP 39水平升高与预后不良相关。USP 39促进体外增殖/侵袭和体内肿瘤生长。重要的是，USP 39在卵巢癌细胞中被癌基因蛋白c-MYC转录激活。我们进一步证明了USP 39与核斑点中的剪接体组分共定位。转录组学分析显示，USP 39缺失导致整体受损的剪接，其特征在于跳过外显子和内含子和基因间区域的过度表达。此外，RNA免疫沉淀测序显示USP 39优先结合5′和3′剪接位点附近的外显子-内含子区域。特别是，USP 39促进HMGA 2的有效剪接，从而增加卵巢癌细胞的恶性程度。综上所述，我们的研究结果表明，USP 39在卵巢癌中作为致癌剪接因子发挥作用，并代表了卵巢癌治疗的潜在靶点。
Aberrant expression of splicing factors was found to promote tumorigenesis and the development of human malignant tumors. Nevertheless, the underlying mechanisms and functional relevance remain elusive. We here show that USP39, a component of the spliceosome, is frequently overexpressed in high-grade serous ovarian carcinoma (HGSOC) and that an elevated level of USP39 is associated with a poor prognosis. USP39 promotes proliferation/invasion in vitro and tumor growth in vivo. Importantly, USP39 was transcriptionally activated by the oncogene protein c-MYC in ovarian cancer cells. We further demonstrated that USP39 colocalizes with spliceosome components in nuclear speckles. Transcriptomic analysis revealed that USP39 deletion led to globally impaired splicing that is characterized by skipped exons and overrepresentation of introns and intergenic regions. Furthermore, RNA immunoprecipitation sequencing showed that USP39 preferentially binds to exon-intron regions near 5′ and 3′ splicing sites. In particular, USP39 facilitates efficient splicing of HMGA2 and thereby increases the malignancy of ovarian cancer cells. Taken together, our results indicate that USP39 functions as an oncogenic splicing factor in ovarian cancer and represents a potential target for ovarian cancer therapy.
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影响因子：
--
作者：
Huang Y;Pan XW;Li L;Chen L;Liu X;Lu JL;Zhu XM;Huang H;Yang QW;Ye JQ;Gan SS;Wang LH;Hong Y;Xu DF;Cui XG
通讯作者：
Cui XG
影响因子：
23.9
作者：
Cesana M;Guo MH;Cacchiarelli D;Wahlster L;Barragan J;Doulatov S;Vo LT;Salvatori B;Trapnell C;Clement K;Cahan P;Tsanov KM;Sousa PM;Tazon-Vega B;Bolondi A;Giorgi FM;Califano A;Rinn JL;Meissner A;Hirschhorn JN;Daley GQ
通讯作者：
Daley GQ
影响因子：
64.5
作者：
Ji X;Zhou Y;Pandit S;Huang J;Li H;Lin CY;Xiao R;Burge CB;Fu XD
通讯作者：
Fu XD
影响因子：
16
作者：
Anczuków O;Akerman M;Cléry A;Wu J;Shen C;Shirole NH;Raimer A;Sun S;Jensen MA;Hua Y;Allain FH;Krainer AR
通讯作者：
Krainer AR
影响因子：
2.9
作者：
Dong X;Su H;Jiang F;Li H;Shi G;Fan L
通讯作者：
Fan L