The PRC1 protein RING1B contributes to Ewing sarcoma tumorigenesis by repressing the NaV1.6 sodium channel and modulating the NF-kB pathway, independently of the fusion oncoprotein.

ABSTRACT: Ewing sarcoma (ES) is an aggressive tumor molecularly defined by reciprocal translocations of EWSR1 to an ETS transcription factor. The functions of EZH2 and BMI1, two proteins of the Polycomb group (PcG) of epigenetic repressors, have been previously shown to mediate specific features in EWSR1/ETS-transformed cells. Here we have characterized the expression and function of RING1B, a PcG protein with unique abilities, in ES. RING1B is highly and universally expressed in primary ES tumors. In contrast to EZH2, RING1B expression is independent of both the oncogene and of differentiation agents. RING1B depletion affects heme biosynthesis and hematopoiesis but does not result in a widespread alteration in ES differentiation. Among the unique set of genes regulated upon RING1B depletion, FGF14 and SCN8A, interacting components of the NaV1.6 channel, are two of the most up-regulated genes. Control of FGF14 and SCN8A in ES is specific of RING1B and functionally relevant. The signaling pathway most significantly modulated by RING1B is NF-κB. Indeed, RING1B depletion results in enhanced p105/p50 expression, which specifically sensitizes ES cells to apoptosis by FGFR/SHP2/STAT3 blockade. In conclusion, we show that RING1B is pivotal in ES cells, independently of the fusion oncogene, likely reflecting essential functional traits of the cell-of-origin. 10 samples were analyzed: A4573 transduced with control shRNA; A4573 transduced with shRING1B; A673 transduced with control shRNA; A673 transduced with shRING1B; SK-ES-1 transduced with control shRNA; SK-ES-1 transduced with shRING1B; TC71 transduced with control shRNA; TC71 transduced with shRING1B; A673 transduced with shBMI1; TC71 transduced with shBMI1

ORGANISM(S): Homo sapiens

SUBMITTER: Lara Nonell 

PROVIDER: E-GEOD-71007 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress