Transcriptomic analysis of CIC and ATXN1L reveal a functional relationship exploited by cancer

Abstract

Aberrations in Capicua (CIC) have recently been implicated as a negative prognostic factor in a multitude of cancer types through activation of the MAPK signalling cascade and derepression of oncogenic ETS transcription factors. The Ataxin-family protein ATXN1L has previously been reported to interact with CIC in developmental and disease contexts to facilitate the repression of CIC target genes. To further investigate this relationship, we performed functional in vitro studies utilizing ATXN1L and CIC human cell lines and characterized a reciprocal functional relationship between CIC and ATXN1L. Transcriptomic interrogation of the CIC-ATXN1-ATXN1L axis in low-grade glioma, prostate adenocarcinoma and stomach adenocarcinoma TCGA cohorts revealed context-dependent convergence of gene sets and pathways related to mitotic cell cycle and division. This study highlights the CIC-ATXN1-ATXN1L axis as a more potent regulator of the cell cycle than previously appreciated.

Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer

“…One intriguing finding is high upregulation in responders of BOAT (gene symbol=ATXN1 L), which cooperates with Capicua (CIC, also upregulated in these patients) in cell cycle regulation. 24 Similarly, the volcano plot for the combination therapy arm (see online supplementary figure S1b) shows many differences; one of these, with modest fold-change but apparent high significance, is TBX21 (T-bet), a Th1 cell-specific transcription factor that controls the expression of IFN-γ. We also performed Spearman's correlations between paired differences in PB GEP data and two quantitative measures of response (percentage tumor size reduction by RECIST, and reduction in serum CA 19-9 for CA 19-9-expressing tumors), but failed to observe compelling implication of genes or processes driving responses (data not shown).…”

Regulation and function of capicua in mammals

“…ATXN1L plays a more pivotal role in the stabilization of CIC than ATXN1; CIC levels decreased more substantially in response to the loss of ATXN1L than to the loss of ATXN1, leading to substantial derepression of CIC target gene expression 31,61 . In the absence of ATXN1L, CIC becomes unstable, resulting in proteasomal degradation 61 . ATXN1L also promotes CIC binding to the target gene promoter regions 61 .…”

“…In the absence of ATXN1L, CIC becomes unstable, resulting in proteasomal degradation 61 . ATXN1L also promotes CIC binding to the target gene promoter regions 61 . However, the reason for the relative importance of ATXN1L for CIC stabilization and function is unclear.…”

TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L

“…In glioblastoma, CIC inactivation occurs as a result of ERK phosphorylation and subsequent degradation through interaction with the E3-ligase PJA1 [ 14 ] or promotes nuclear export by the kinase c-Src [ 24 ]. Conversely, dysregulation of CIC through loss of ATXN1L has been observed in several other cancer subtypes including low-grade glioma and prostate, stomach, pancreatic, gastric, and lung adenocarcinomas [ 17 , 25 ].…”

“…ATXN1L is a member of the Ataxin protein family which has been shown to be a potent regulator of CIC function in both development and cancer [ 17 , 25 , 26 ]. Previous studies investigating murine development have indicated some level of functional redundancy between ATXN1L and its homolog ATXN1.…”