Takemon Yuka, LeBlanc Véronique G, Song Jungeun, Chan Susanna Y, Lee Stephen Dongsoo, Trinh Diane L, Ahmad Shiekh Tanveer, Brothers William R, Corbett Richard D, Gagliardi Alessia, Moradian Annie, Cairncross J Gregory, Yip Stephen, Aparicio Samuel A J R, Chan Jennifer A, Hughes Christopher S, Morin Gregg B, Gorski Sharon M, Chittaranjan Suganthi, Marra Marco A
Genome Science and Technology Graduate Program, University of British Columbia, Vancouver, BC V5Z 4S6, Canada.
Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada.
Cancers (Basel). 2023 May 17;15(10):2805. doi: 10.3390/cancers15102805.
encodes a transcriptional repressor and MAPK signalling effector that is inactivated by loss-of-function mutations in several cancer types, consistent with a role as a tumour suppressor. Here, we used bioinformatic, genomic, and proteomic approaches to investigate CIC's interaction networks. We observed both previously identified and novel candidate interactions between CIC and SWI/SNF complex members, as well as novel interactions between CIC and cell cycle regulators and RNA processing factors. We found that CIC loss is associated with an increased frequency of mitotic defects in human cell lines and an in vivo mouse model and with dysregulated expression of mitotic regulators. We also observed aberrant splicing in CIC-deficient cell lines, predominantly at 3' and 5' untranslated regions of genes, including genes involved in MAPK signalling, DNA repair, and cell cycle regulation. Our study thus characterises the complexity of CIC's functional network and describes the effect of its loss on cell cycle regulation, mitotic integrity, and transcriptional splicing, thereby expanding our understanding of CIC's potential roles in cancer. In addition, our work exemplifies how multi-omic, network-based analyses can be used to uncover novel insights into the interconnected functions of pleiotropic genes/proteins across cellular contexts.
编码一种转录抑制因子和丝裂原活化蛋白激酶（MAPK）信号传导效应器，在几种癌症类型中因功能丧失突变而失活，这与它作为肿瘤抑制因子的作用一致。在这里，我们使用生物信息学、基因组学和蛋白质组学方法来研究CIC的相互作用网络。我们观察到CIC与SWI/SNF复合体成员之间既有先前已确定的相互作用，也有新的候选相互作用，以及CIC与细胞周期调节因子和RNA加工因子之间的新相互作用。我们发现，在人类细胞系和体内小鼠模型中，CIC缺失与有丝分裂缺陷频率增加以及有丝分裂调节因子的表达失调有关。我们还在CIC缺陷的细胞系中观察到异常剪接，主要发生在基因的3'和5'非翻译区，包括参与MAPK信号传导、DNA修复和细胞周期调节的基因。因此，我们的研究描述了CIC功能网络的复杂性，并描述了其缺失对细胞周期调节、有丝分裂完整性和转录剪接的影响，从而扩展了我们对CIC在癌症中潜在作用的理解。此外，我们的工作例证了如何使用基于多组学网络的分析来揭示跨细胞环境中多效性基因/蛋白质相互关联功能的新见解。
