The CIC-ERF co-deletion underlies fusion-independent activation of ETS family member, ETV1, to drive prostate cancer progression

Abstract

Human prostate cancer can result from chromosomal rearrangements that lead to aberrant ETS gene expression. The mechanisms that lead to fusion-independent ETS factor upregulation and prostate oncogenesis remain relatively unknown. Here, we show that two neighboring transcription factors, Capicua (CIC) and ETS2 repressor factor (ERF), which are co-deleted in human prostate tumors can drive prostate oncogenesis. Concurrent CIC and ERF loss commonly occur through focal genomic deletions at chromosome 19q13.2. Mechanistically, CIC and ERF co-bind the proximal regulatory element and mutually repress the ETS transcription factor, ETV1. Targeting ETV1 in CIC and ERF-deficient prostate cancer limits tumor growth. Thus, we have uncovered a fusion-independent mode of ETS transcriptional activation defined by concurrent loss of CIC and ERF.

Oncogenic signaling in the adultDrosophilaprostate-like accessory gland leads to activation of a conserved pro-tumorigenic program, in the absence of proliferation

“…In Drosophila , Ets21C is upregulated in response to JNK signaling (Kulshammer et al, 2015; Toggweiler et al, 2016) as well as inactivation of the transcriptional repressor capicua (Jin et al, 2015). Here we show JNK signaling is increased in prostate cancer polyaneuploid cells and human Capicua (Cic) has been shown to be a tumor suppressor in prostate cancer (Gupta et al, 2022; Seim et al, 2017), suggesting the Drosophila accessory gland recapitulates key signaling features of the human cancer, despite the postmitotic state of the fly prostate-like cells. Capicua function is downregulated by Ras/Map Kinase signaling, through degradation, nuclear export, or both (Astigarraga et al, 2007; Grimm et al, 2012; Jin et al, 2015; Roch et al, 2002; Tseng et al, 2007).…”

“…Their short lifespan, low cost of maintenance and the conservation of many tumorigenic signaling pathways, have led to a robust field of study using Drosophila models to investigate the cellular biology and genetics of tumorigenesis across tissues and developmental stages (Dow and Romero, 2010;Moraes and Montagne, 2021;Verheyen, 2022). This is facilitated by tools that allow spatio-temporal control over genetic manipulations including inducible over-expression or gene knockdown through RNAi as well as mosaic loss-of-function and gain-offunction tools (Bangi et al, 2016;Harnish et al, 2021;Sonoshita and Cagan, 2017;Zirin et al, 2020).…”

Multi-Omic Analysis of CIC’s Functional Networks Reveals Novel Interaction Partners and a Potential Role in Mitotic Fidelity

“…Similar to CIC, loss of ERF has been linked to dysregulation of the cell cycle [69], developmental delays, and intellectual disability [71]. ERF and CIC were also recently shown to coordinate to regulate ETV1 expression in prostate cancer cells [72], further supporting the notion that the two proteins function similarly and, at least in one context, cooperatively. Interestingly given CIC having recently been shown to interact with the SWI/SNF complex to regulate neuronal maturation [32], the co-essential and co-expressed gene BICRA encodes the SWI/SNF complex member GLTSCR1 [73], further strengthening functional associations between CIC and the SWI/SNF complex.…”

“…For example, CIC's co-essential network, which is composed of genes with which CIC is likely to share functionality, included several known regulators of MAPK signalling, including DUSP6, RASA1, and ERF. Notably, CIC and ERF have been shown to co-regulate the expression of ETV1 in prostate cancer, where their combined loss and the subsequent increase in ETV1 expression contribute to disease progression [72]. As mentioned above, the two genes, which are located directly adjacent to one another on chromosome 19q, are co-deleted in 1p/19q co-deleted low-grade gliomas and also frequently in prostate adenocarcinomas (~10-12% of cases) [72], suggesting that the dual loss of CIC and ERF (possibly with BICRA/GLTSCR1, as discussed above) may favour tumour development, possibly through their combined dysregulation of MAPK signalling.…”

“…Notably, CIC and ERF have been shown to co-regulate the expression of ETV1 in prostate cancer, where their combined loss and the subsequent increase in ETV1 expression contribute to disease progression [72]. As mentioned above, the two genes, which are located directly adjacent to one another on chromosome 19q, are co-deleted in 1p/19q co-deleted low-grade gliomas and also frequently in prostate adenocarcinomas (~10-12% of cases) [72], suggesting that the dual loss of CIC and ERF (possibly with BICRA/GLTSCR1, as discussed above) may favour tumour development, possibly through their combined dysregulation of MAPK signalling. Further studies aimed at distinguishing the joint and distinct roles of CIC and ERF are thus warranted in order to reveal the extent and implication of their cooperative roles.…”