Aberrations in Capicua (CIC) have recently been implicated as a negative prognostic factor in a multitude of cancer types through the derepression of targets downstream of the mitogen-activated protein kinase (MAPK) signaling cascade, such as oncogenic E26 transformation-specific (ETS) transcription factors. The Ataxin-family protein ATXN1L has previously been reported to interact with CIC in both developmental and disease contexts to facilitate the repression of CIC target genes and promote the post-translational stability of CIC. However, little is known about the mechanisms at the base of ATXN1L-mediated CIC post-translational stability. Functional in vitro studies utilizing ATXN1LKO human cell lines revealed that loss of ATXN1L leads to the accumulation of polyubiquitinated CIC protein, promoting its degradation through the proteasome. Although transcriptomic signatures of ATXN1LKO cell lines indicated upregulation of the mitogen-activated protein kinase pathway, ERK activity was found to contribute to CIC function but not stability. Degradation of CIC protein following loss of ATXN1L was instead observed to be mediated by the E3 ubiquitin ligase TRIM25 which was further validated using glioma-derived cell lines and the TCGA breast carcinoma and liver hepatocellular carcinoma cohorts. The post-translational regulation of CIC through ATXN1L and TRIM25 independent of ERK activity suggests that the regulation of CIC stability and function is more intricate than previously appreciated and involves several independent pathways. As CIC status has become a prognostic factor in several cancer types, further knowledge into the mechanisms which govern CIC stability and function may prove useful for future therapeutic approaches.

中文翻译：

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在没有ATXN1L的情况下，TRIM25可以独立于ERK促进Capicua降解

最近，通过降低有丝分裂原激活的蛋白激酶（MAPK）信号级联反应下游靶标的抑制，例如致癌性E26特异性转化（ETS），Capicua畸变（CIC）被认为是多种癌症的阴性预后因素。转录因子。先前已经报道了抗紫杉素家族蛋白ATXN1L在发育和疾病背景下均与CIC相互作用，以促进CIC靶基因的抑制并促进CIC的翻译后稳定性。但是，关于ATXN1L介导的CIC翻译后稳定性基础的机制知之甚少。利用ATXN1LKO人类细胞系进行的功能性体外研究表明，ATXN1L的缺失会导致多泛素化CIC蛋白的积累，从而促进其通过蛋白酶体的降解。尽管ATXN1LKO细胞系的转录组特征表明有丝分裂原激活的蛋白激酶途径上调，但发现ERK活性有助于CIC功能，但不能稳定。相反，观察到ATXN1L丢失后CIC蛋白的降解是由E3泛素连接酶TRIM25介导的，这已使用胶质瘤来源的细胞系以及TCGA乳腺癌和肝肝细胞癌队列进一步证实。通过ATXN1L和TRIM25独立于ERK活性对CIC进行翻译后调节，表明CIC稳定性和功能的调节比以前理解的更为复杂，并且涉及几个独立的途径。由于CIC状况已成为多种癌症类型的预后因素，