RBM4 dictates ESCC cell fate switch from cellular senescence to glutamine-addiction survival through inhibiting LKB1-AMPK-axis.

Cellular senescence provides a protective barrier against tumorigenesis in precancerous or normal tissues upon distinct stressors. However, the detailed mechanisms by which tumor cells evade premature senescence to malignant progression remain largely elusive. Here we reported that RBM4 adversely impacted cellular senescence to favor glutamine-dependent survival of esophageal squamous cell carcinoma (ESCC) cells by dictating the activity of LKB1, a critical governor of cancer metabolism. The level of RBM4 was specifically elevated in ESCC compared to normal tissues, and RBM4 overexpression promoted the malignant phenotype. RBM4 contributed to overcome H-RAS- or doxorubicin-induced senescence, while its depletion caused P27-dependent senescence and proliferation arrest by activating LKB1-AMPK-mTOR cascade. Mechanistically, RBM4 competitively bound LKB1 to disrupt the LKB1/STRAD/MO25 heterotrimeric complex, subsequently recruiting the E3 ligase TRIM26 to LKB1, promoting LKB1 ubiquitination and degradation in nucleus. Therefore, such molecular process leads to bypassing senescence and sustaining cell proliferation through the activation of glutamine metabolism. Clinically, the ESCC patients with high RBM4 and low LKB1 have significantly worse overall survival than those with low RBM4 and high LKB1. The RBM4 high/LKB1 low expression confers increased sensitivity of ESCC cells to glutaminase inhibitor CB-839, providing a novel insight into mechanisms underlying the glutamine-dependency to improve the efficacy of glutamine inhibitors in ESCC therapeutics.

Loss of RBMS1 promotes anti-tumor immunity through enabling PD-L1 checkpoint blockade in triple-negative breast cancer.

Immunotherapy has been widely utilized in multiple tumors, however, its efficacy in the treatment of triple-negative breast cancers (TNBC) is still being challenged. Meanwhile, functions and mechanisms of RNA binding proteins in regulating immunotherapy for TNBC remain largely elusive. Here we reported that the RNA binding protein RBMS1 is prevalent among immune-cold TNBC. Through a systematic shRNA-mediated screen, we found depletion of RBMS1 significantly reduced the level of programmed death ligand 1 (PD-L1) in TNBC. Clinically, RBMS1 was increased in breast cancer and its level was positively correlated to that of PD-L1. RBMS1 ablation stimulated cytotoxic T cell mediated anti-tumor immunity. Mechanistically, RBMS1 regulated the mRNA stability of B4GALT1, a newly identified glycosyltransferase of PD-L1. Depletion of RBMS1 destabilized the mRNA of B4GALT1, inhibited the glycosylation of PD-L1 and promoted the ubiquitination and subsequent degradation of PD-L1. Importantly, combination of RBMS1 depletion with CTLA4 immune checkpoint blockade or CAR-T treatment enhanced anti-tumor T-cell immunity both in vitro and in vivo. Together, our findings provided a new immunotherapeutic strategy against TNBC by targeting the immunosuppressive RBMS1.