Inhibition of DUSP18 impairs cholesterol biosynthesis and promotes anti-tumor immunity in colorectal cancer.

Tumor cells reprogram their metabolism to produce specialized metabolites that both fuel their own growth and license tumor immune evasion. However, the relationships between these functions remain poorly understood. Here, we report CRISPR screens in a mouse model of colo-rectal cancer (CRC) that implicates the dual specificity phosphatase 18 (DUSP18) in the establishment of tumor-directed immune evasion. Dusp18 inhibition reduces CRC growth rates, which correlate with high levels of CD8+ T cell activation. Mechanistically, DUSP18 dephosphorylates and stabilizes the USF1 bHLH-ZIP transcription factor. In turn, USF1 induces the SREBF2 gene, which allows cells to accumulate the cholesterol biosynthesis intermediate lanosterol and release it into the tumor microenvironment (TME). There, lanosterol uptake by CD8+ T cells suppresses the mevalonate pathway and reduces KRAS protein prenylation and function, which in turn inhibits their activation and establishes a molecular basis for tumor cell immune escape. Finally, the combination of an anti-PD-1 antibody and Lumacaftor, an FDA-approved small molecule inhibitor of DUSP18, inhibits CRC growth in mice and synergistically enhances anti-tumor immunity. Collectively, our findings support the idea that a combination of immune checkpoint and metabolic blockade represents a rationally-designed, mechanistically-based and potential therapy for CRC.

Phosphomevalonate Kinase Controls ß-Catenin Signaling via the Metabolite 5-Diphosphomevalonate.

ß-catenin signaling is abnormally activated in cancer. Here, this work screens the mevalonate metabolic pathway enzyme PMVK to stabilize ß-catenin signaling using a human genome-wide library. On the one hand, PMVK-produced MVA-5PP competitively binds to CKIα to prevent ß-catenin Ser45 phosphorylation and degradation. On the other hand, PMVK functions as a protein kinase to directly phosphorylate ß-catenin Ser184 to increase its protein nuclear localization. This synergistic effect of PMVK and MVA-5PP together promotes ß-catenin signaling. In addition, PMVK deletion impairs mouse embryonic development and causes embryonic lethal. PMVK deficiency in liver tissue alleviates DEN/CCl4 -induced hepatocarcinogenesis. Finally, the small molecule inhibitor of PMVK, PMVKi5, is developed and PMVKi5 inhibits carcinogenesis of liver and colorectal tissues. These findings reveal a non-canonical function of a key metabolic enzyme PMVK and a novel link between the mevalonate pathway and ß-catenin signaling in carcinogenesis providing a new target for clinical cancer therapy.

p53 promotes peroxisomal fatty acid ß-oxidation to repress purine biosynthesis and mediate tumor suppression.

The metabolic pathways through which p53 functions as a potent tumor suppressor are incompletely understood. Here we report that, by associating with the Vitamin D receptor (VDR), p53 induces numerous genes encoding enzymes for peroxisomal fatty acid ß-oxidation (FAO). This leads to increased cytosolic acetyl-CoA levels and acetylation of the enzyme 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC), which catalyzes the last two steps in the purine biosynthetic pathway. This acetylation step, mediated by lysine acetyltransferase 2B (KAT2B), occurs at ATIC Lys 266, dramatically inhibits ATIC activity, and inversely correlates with colorectal cancer (CRC) tumor growth in vitro and in vivo, and acetylation of ATIC is downregulated in human CRC samples. p53-deficient CRCs with high levels of ATIC is more susceptible to ATIC inhibition. Collectively, these findings link p53 to peroxisomal FAO, purine biosynthesis, and CRC pathogenesis in a manner that is regulated by the levels of ATIC acetylation.

[Clinical observation of ankylosing spondylitis treated with moxibustion along the governor vessel and the conception vessel and salazosulfapyridine].

OBJECTIVE: To observe the difference in the clinical efficacy on ankylosing spondylitis (AS) between the combined therapy of moxibustion along the governor vessel and the conception vessel and salazosulfapyridine (SASP) and the routine moxibustion. METHODS: Sixty-two patients of AS were randomized into two groups, 31 cases in each one with one case dnopping separately. In the two groups, SASP was prescribed for oral administration. In the observation group, the self-prepared moxa powder, ginger granules and moxa wool were placed on the back, from Dazhui (GV 14) to Yaoshu (GV 2) and on the abdomen, from the inferior of the xiphoid process to the upper border of symphsis pubis, covering the running of the governor vessel and the conception vessel. In the control group, the routine moxibustion therapy was used, in which, the moxa box was placed on the back and abdomen alternatively. Each treatment lasted 2 h, once every 7 days, 3 treatments as one session. After 3 sessions of treatment, the symptom score, visual analogue scale (VAS) score, time of morning stiffness, Schober test, occiput-to-wall distance and thoracic mobility were observed before and after treatment. The clinical efficacy was evaluated in the two groups. RESULTS: The total effective rate was 86.7% (26/30) in the observation group, better than 73.3% (22/30) in the control group. The efficacy in the observation group was better than that in the control group (P<0.05). All of the observation indices after treatment were improved apparently as compared with those before treatment in the two groups (all P<0.01). After treatment, the improvements in the symptom score, VAS score, time of morning stiffness and Schober test in the observation group were better apparently than those in the control group (all P<0.01). CONCLUSIONS: On the basis of treatment with SASP, moxibustion along the governor vessel and the conception vessel achieves the definite efficacy on AS, better than the routine moxibustion therapy.