MYC shapes ER-mitochondria calcium transfer by directly targeting ITPR1: implications for MYC-induced safeguard mechanisms and cancer

The MYC and NMYC transcription factors (TFs) play a key role in cell proliferation and are overexpressed in most cancer cells. However, in normal cells their overexpression triggers safeguard mechanisms promoting cell death and cellular senescence, which are bypassed in cancer cells. The mechanisms of action of this TF family are only partially understood. Here, we reveal that in normal cells MYC binds to the Inositol 1,4,5-Trisphosphate Receptor type 1 (ITPR1) gene and upregulates its expression, triggering an ER-mitochondria calcium (Ca2+) transfer, which is involved in MYC-induced cell death and senescence. Supporting a tumor suppressive role of MYC/ITPR1 axis, ITPR1 expression is generally decreased in cancer and reactivation of this pathway induces cancer cell death. Nevertheless, some cancer cells, generally expressing high levels of MYCN and/or MYC, also express high level of ITPR1, which correlates with high expression of BCL2, encoding an inhibitor of ITPR1. Strikingly, in high-risk MYCN-amplified neuroblastoma, ITPR1 expression is controlled by NMYC and its level correlates with worse patient survival. In these cells, blocking the interaction between BCL2 and ITPR1 induces mitochondrial Ca2+ accumulation and cell death, and decreases tumor size. Collectively these data highlight a new function of MYC factors by controlling Ca2+ signaling, which could constitute an unsuspected vulnerability for some cancer cells, including high-risk MYCN-amplified neuroblastoma cells.