Abstract
BackgroundAberrations 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.ResultsFunctional 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.ConclusionsThe 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.
Highlights
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
Loss of ATXN1L promotes the proteasomal degradation of CIC Several studies in human cell lines and mouse studies have reported decreased CIC protein expression following the loss of ATXN1L [17, 25, 26]
In concordance with these studies, decreased CIC protein expression was observed in our ATXN1LKO cell lines [25] which could be partially rescued to levels similar to the untreated parental cell line following treatment with MG132, an inhibitor of the 20S subunit of the proteasome (Fig. 1a), or ectopic expression of a FLAG-tagged ATXN1L construct (Fig. 1b)
Summary
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. Dysregulation of CIC activity has been associated with negative prognostic features and/or oncogenesis in several human cancer types [12] including sarcoma [13], glioblastoma [14], hepatocellular carcinoma [15] lung adenocarcinoma [16], and pancreatic adenocarcinoma [17]. This may be due to the subsequent upregulation of RTK-responsive genes such as the oncogenic ETS transcription factors (ETV1/4/5) [15,16,17,18,19,20,21,22,23]. Dysregulation of CIC through loss of ATXN1L has been observed in several other cancer subtypes including lowgrade glioma and prostate, stomach, pancreatic, gastric, and lung adenocarcinomas [17, 25]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
