CDK12 orchestrates super-enhancer-associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer.
CDK12 orchestrates super-enhancer-associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer.
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CDK12协调超级增强子相关的CCDC137转录以指导结直肠癌的肝转移
DOI：
10.1002/ctm2.1087
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发表时间：
2022-10
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
由于缺乏有效的治疗靶点，肝转移是导致结直肠癌（CRC）患者死亡的主要和直接原因。本研究旨在确定肝转移性CRC患者的潜在药物候选靶点。在可公开访问的CRC数据集中评估了原发性和肝转移性CRC中超级增强子（SE）的转录谱。进行人CRC组织的免疫组织化学以确定CDK 12的表达水平。通过多种体外和体内试验，检查了shCDK 12或选择性CDK 12抑制剂SR-4835抑制CDK 12后的细胞增殖、存活和干性。进行RNA测序和生物信息学分析以研究CRC细胞中CDK 12抑制的机制。我们鉴定了CDK 12作为CRC中直接肝转移的驱动基因。CDK 12的抑制导致对增殖、存活和干性的强烈抑制。从机制上讲，CDK 12干预优先抑制SE相关基因的转录。整合SE景观和RNA测序，BCL 2L 1和CCDC 137被确定为SE相关的致癌基因，以加强细胞存活，增殖和干性的能力，最终增加CRC的肝转移。我们的数据强调了CDK 12和SE相关致癌转录物作为肝转移性CRC患者治疗靶点的潜力。超级增强子通过驱动超级增强子相关基因BCL 2L 1和CCDC 137的过表达来促进CRC细胞中转移相关的细胞特征（增殖、存活、干性）。通过SR 4835或shRNA慢病毒抑制CDK 12来破坏SE，通过下调相关基因的转录来有效地消除肝转移。CCDC 137促进CRC中的增殖和癌症干细胞样细胞。
Hepatic metastasis is the primary and direct cause of death in individuals with colorectal cancer (CRC) attribute to lack of effective therapeutic targets. The present study aimed to identify potential druggable candidate targets for patients with liver metastatic CRC. The transcriptional profiles of super‐enhancers (SEs) in primary and liver metastatic CRC were evaluated in publicly accessible CRC datasets. Immunohistochemistry of human CRC tissues was conducted to determine the expression level of CDK12. Cellular proliferation, survival and stemness were examined upon CDK12 inhibition by shCDK12 or a selective CDK12 inhibitor named SR‐4835 with multiple in vitro and in vivo assays. RNA sequencing and bioinformatics analyses were carried out to investigate the mechanisms of CDK12 inhibition in CRC cells. We identified CDK12 as a driver gene for direct hepatic metastasis in CRC. Suppression of CDK12 led to robust inhibition of proliferation, survival and stemness. Mechanistically, CDK12 intervention preferentially repressed the transcription of SE‐associated genes. Integration of the SE landscape and RNA sequencing, BCL2L1 and CCDC137 were identified as SE‐associated oncogenic genes to strengthen the abilities of cellular survival, proliferation and stemness, eventually increasing liver metastasis of CRC. Our data highlight the potential of CDK12 and SE‐associated oncogenic transcripts as therapeutic targets for patients with liver metastatic CRC. Super‐enhancers fostered metastasis‐related cellular features (proliferation, survival, stemness) in CRC cells via driving overexpression of super enhancer‐associate genes BCL2L1 and CCDC137. Disruption of SEs by CDK12 inhibition with SR4835 or shRNA lentivirus efficiently eliminated liver metastasis through downregulating transcription of relevant genes. CCDC137 promotes proliferation and cancer stem‐like cells in CRC.
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影响因子：
64.8
作者：
Konermann S;Brigham MD;Trevino AE;Joung J;Abudayyeh OO;Barcena C;Hsu PD;Habib N;Gootenberg JS;Nishimasu H;Nureki O;Zhang F
通讯作者：
Zhang F
影响因子：
3.4
作者：
Lui GYL;Grandori C;Kemp CJ
通讯作者：
Kemp CJ
影响因子：
14.9
作者：
Huang M;Chen Y;Yang M;Guo A;Xu Y;Xu L;Koeffler HP
通讯作者：
Koeffler HP
影响因子：
8
作者：
Liu, Shenglan;He, Liangmei;Liu, Zhiping
通讯作者：
Liu, Zhiping
影响因子：
3.7
作者：
Makondi PT;Chu CM;Wei PL;Chang YJ
通讯作者：
Chang YJ