Targeting TRIM24 promotes neuroblastoma differentiation and decreases tumorigenicity via LSD1/CoREST complex

High-risk neuroblastoma (NB) still has an unfavorable prognosis and inducing NB differentiation is a potential strategy for clinical treatment, yet underlying mechanisms are still elusive. Here we identify TRIM24 as an important regulator of NB differentiation. Trim24 was highly expressed in spontaneous NB in TH-MYCN transgenic mice and clinical NB specimens. And it was associated with poor NB differentiation and functioned as an unfavorable prognostic factor. Knockout of TRIM24 in MYCN-amplified neuroblastoma cells promoted cell differentiation and reduced cell stemness, cell colony formation in soft agar and subcutaneous xenograft tumor growth in nude mice. Mechanistic investigations demonstrated that TRIM24 knockout activated retinoic acid pathway and suppressed LSD1/CoREST complex formation and inhibited the transcription of genes involved in NB differentiation such as ZIC4. Targeting TRIM24 in combination with retinoic acid (RA) synergistically promoted NB cell differentiation and inhibited cell viability. Taken together, Our findings demonstrate that TRIM24 is critical for NB differentiation and suggest that TRIM24 is a promising therapeutic target in combination with RA in NB differentiation therapy.