A SNARE geranylgeranyltransferase essential for the organization of the Golgi apparatus.

Protein prenylation is essential for many cellular processes including signal transduction, cytoskeletal reorganization, and membrane trafficking. Here, we identify a novel type of protein prenyltransferase, which we named geranylgeranyltransferase type-III (GGTase-III). GGTase-III consists of prenyltransferase alpha subunit repeat containing 1 (PTAR1) and the ß subunit of RabGGTase. Using a biotinylated geranylgeranyl analogue, we identified the Golgi SNARE protein Ykt6 as a substrate of GGTase-III. GGTase-III transfers a geranylgeranyl group to mono-farnesylated Ykt6, generating doubly prenylated Ykt6. The crystal structure of GGTase-III in complex with Ykt6 provides structural basis for Ykt6 double prenylation. In GGTase-III-deficient cells, Ykt6 remained in a singly prenylated form, and the Golgi SNARE complex assembly was severely impaired. Consequently, the Golgi apparatus was structurally disorganized, and intra-Golgi protein trafficking was delayed. Our findings reveal a fourth type of protein prenyltransferase that generates geranylgeranyl-farnesyl Ykt6. Double prenylation of Ykt6 is essential for the structural and functional organization of the Golgi apparatus.

Different impacts of TP53 mutations on cell cycle-related gene expression among cancer types.

Functional properties caused by TP53 mutations are involved in cancer development and progression. Although most of the mutations lose normal p53 functions, some of them, gain-of-function (GOF) mutations, exhibiting novel oncogenic functions. No reports have analyzed the impact of TP53 mutations on the gene expression profile of the p53 signaling pathway across cancer types. This study is a cross-cancer type analysis of the effects of TP53 mutations on gene expression. A hierarchical cluster analysis of the expression profile of the p53 signaling pathway classified 21 cancer types into two clusters (A1 and A2). Changes in the expression of cell cycle-related genes and MKI67 by TP53 mutations were greater in cluster A1 than in cluster A2. There was no distinct difference in the effects between GOF and non-GOF mutations on the gene expression profile of the p53 signaling pathway.

TP53 Gain-of-Function Mutation is a Poor Prognostic Factor in High-Methylated Metastatic Colorectal Cancer.

BACKGROUND: Neither TP53 mutation nor DNA methylation status has been established as a biomarker alone of metastatic colorectal cancer. We analyzed the association between TP53 mutation functional subtypes and genome-wide DNA methylation status (GWMS) as combined prognostic markers. METHODS: Patient clinical data were obtained from the TRICOLORE study, a randomized phase III trial. The TP53 mutations were classified into wild-type, gain-of-function (GOF) mutations, and non-gain-of-function (non-GOF) mutations. GWMS of the tumor tissues classified them into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). Overall survival (OS) was compared based on these subgroups. RESULTS: Of the 209 patients, 60 (28.7%) were HMCC and 149 (71.3%) were LMCC, 35 (16.7%) were TP53 wild-type and 174 (83.3%) were TP53 mutants including 79 (45.4%) GOF mutations and 95 (54.6%) non-GOF mutations. The OS of the HMCC group was shorter than that of the LMCC group (median 25.3 vs. 40.3 months, P < .001, hazard ratio 1.87) in the total cohort. The combined subgroup analyses of GWMS and TP53 mutation subtypes showed that the HMCC/GOF group had significantly shorter OS than the HMCC/non-GOF group, the LMCC/GOF group, and the LMCC/non-GOF group (median 17.7; 35.3, 40.3, and 41.2 months, P = .007, P < .001, and P < .001, respectively), regardless of the primary tumor location. By the multivariate analysis, only HMCC (P = .009) was a poor prognostic factor in the GOF mutation group. CONCLUSIONS: TP53 GOF with HMCC is a newly identified poorest prognostic molecular subset in metastatic colorectal cancer.

Antibiotic Treatment Improves the Efficacy of Oxaliplatin-Based Therapy as First-Line Chemotherapy for Patients with Advanced Gastric Cancer: A Retrospective Study.

Purpose: One of the first-line treatment for gastric cancer patients is oxaliplatin, and the efficacy of this chemotherapeutic can be attenuated by the microbiome. In this study, we retrospectively evaluated whether treatment with antibiotics improved the efficacy of oxaliplatin-based chemotherapy in patients with advanced gastric cancer. Patients and Methods: Fifty-four patients were assigned to the antibiotic-treated group and 35 to the antibiotic-untreated group. Results: The response rate of oxaliplatin-based chemotherapy in the antibiotic-treated and antibiotic-untreated groups was 66.7% and 41.4%, respectively (p = 0.038). The median progression-free survival after oxaliplatin-based chemotherapy in the antibiotic-treated and antibiotic-untreated groups was 8.8 and 5.2 months, respectively (hazard ratio = 0.456, 95% confidence interval = 0.254-0.819; p = 0.007, Log rank test). Univariate and multivariate analyses revealed that antibiotic treatment was the only clinical parameter that correlated with the response to oxaliplatin. Conclusion: Antibiotic treatment could be used therapeutically to enhance the efficacy of oxaliplatin-based chemotherapy in patients with advanced gastric cancer.