Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane-associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC.

Dysregulation of mRNA translation, including preferential translation of mRNA with complex 5'-UTRs such as the MYC oncogene, is recognized as an important mechanism in cancer. In this study, we show that both human and murine chronic lymphocytic leukemia (CLL) cells display a high translation rate, which can be inhibited by the synthetic flavagline FL3, a prohibitin (PHB)-binding drug. A multiomics analysis consisting of pulsed SILAC, RNA sequencing and polysome profiling performed in CLL patient samples and cell lines treated with FL3 revealed the decreased translation of the MYC oncogene and of proteins involved in cell cycle and metabolism. Furthermore, inhibition of translation was associated with a block of proliferation and a profound rewiring of MYC-driven metabolism. Interestingly, contrary to other models, the RAS-RAF-(PHBs)-MAPK pathway is neither impaired by FL3 nor implicated in translation regulation in CLL cells. Here, we rather show that PHBs are directly associated with the translation initiation complex and can be targeted by FL3. Knock-down of PHBs resembled FL3 treatment. Importantly, inhibition of translation was efficient in controlling CLL development in vivo either alone or combined with immunotherapy. Finally, high expression of translation initiation-related genes and PHBs genes correlated with poor survival and unfavorable clinical parameters in CLL patients. In conclusion, we demonstrated that translation inhibition is a valuable strategy to control CLL development by blocking the translation of several oncogenic pathways including MYC. We also unraveled a new and direct role of PHBs in translation initiation, thus creating new therapeutic opportunities for CLL patients.

We investigated the role of amino acid metabolism (AAM) in head and neck squamous cell carcinoma (HNSCC) tissues to explore its prognostic value and potential therapeutic strategies. A risk score based on four AAM-related genes (AMG) was constructed that could predict the prognosis of HNSCC. These four genes were up-regulated in HNSCC tissues and might act as oncogenes. Internal validation in The Cancer Genome Atlas (TCGA) by bootstrapping showed that patients with high-risk scores had a poorer prognosis than patients with low-risk scores, and this was confirmed in the Gene Expression Omnibus (GEO) cohort. There were also differences between the high-risk and low-risk groups in clinical information and different anatomical sites such as age, sex, TNM stage, grade stage, surgery or no surgery, chemotherapy, radiotherapy, no radiotherapy, neck lymph node dissection or not, and neck lymphovascular invasion, larynx, overlapping lesion of lip, and oral cavity and pharynx tonsil of overall survival (OS). Immune-related characteristics, tumor microenvironment (TME) characteristics, and immunotherapy response were significantly different between high- and low-risk groups. The four AMGs were also found to be associated with the expression of markers of various immune cell subpopulations. Therefore, our comprehensive approach revealed the characterization of AAM in HNSCC to predict prognosis and guide clinical therapy.

Primary immune thrombocytopenia (ITP) is the most common acquired autoimmune bleeding disorder. Abnormally increased levels of High Mobility Group Box 1 Protein (HMGB1) associate with thrombocytopenia and therapeutic outcome in ITP. Previous studies proposed that a natural inhibitor of HMGB1, 18β-glycyrrhetinic acid (18β-GA), has been used for its anti-inflammatory and immune-modulatory effects, although its capability of correcting immune balance in ITP is unclear. In this study, we discovered that plasma HMGB1 correlated negatively with platelet counts in ITP patients, and confirmed that 18β-GA stimulated the production of regulatory T cells (Tregs), restored the balance of CD4+ T cell subsets and enhanced the suppressive function of Tregs through blocking the effect on HMGB1 in patients with ITP. HMGB1 short hairpin RNA interference masked the effect of 18β-GA in Tregs of ITP patients. Furthermore, we found that 18β-GA alleviated thrombocytopenia in ITP mice. Briefly, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to induce a murine model of severe ITP. The proportion of circulating Tregs significantly increased, while the level of plasma HMGB1 and serum antiplatelet antibodies significantly decreased in ITP mice along 18β-GA treatment. In addition, 18β-GA reduced phagocytic activity of macrophages towards platelets both in ITP patients and ITP mice. These results indicated that 18β-GA has the potential to restore immune balance in ITP via inhibition of HMGB1 signaling. In short, this study reveals the role of HMGB1 in ITP, which may serve as a potential target for thrombocytopenia therapy.

Background:CLL is the most common type of leukemia in adult, and despite great advance in the standard of care in the last decades, there is still no cure available. CLL cells are dependent on their microenvironment for proliferation and survival. Microenvironmental stimuli are associated with an increase in translation globally but also at the level of specific transcripts, including the MYC oncogene. Interestingly, translation was recognized as one "Achilles' heel" of cancer cells and increased translation seems to be a common feature of a large variety of tumors. Several inhibitors of translation are available. We used FL3, a synthetic flavagline that was shown to bind prohibitins (PHBs). These proteins are found in several cellular localizations that dictate their activity. At the membrane, they are required for the RAF activation by RAS in a large variety of cancers, leading to the phosphorylation of eukaryotic initiation factor 4E (eIF4E) through the MAPK pathway, and ultimately resulting in increased translation. By binding to PHBs, FL3 was shown to prevent the activation of RAF and therefore decreases the translation.