Brahma-related gene-1 (BRG1) is the specific ATPase of switch/sucrose nonfermentable chromatin-remodeling complex that is aberrantly expressed or mutated in various cancers. However, the exact role of BRG1 in oncogenesis remains unknown. In this study, we demonstrate that the knockdown (KD) of BRG1 promotes cellular senescence by influencing the SIRT1/p53/p21 signal axis in colorectal cancer (CRC). In particular, we reveal that the expression level of BRG1 is inversely correlated with p21, one of the classic senescence regulators, and is decreased in senescent CRC cells. KD of BRG1 promoting senescence is indicated by the increase of senescence-associated β-galactosidase (SA-β-gal) activity, inhibition of cell proliferation, induction of cell cycle arrest, and formation of senescence-associated heterochromatin foci. BRG1 binds to SIRT1 and interferes with SIRT1-mediated deacetylation of p53 at K382. Rescue experiments by co-silencing p53 or treatment with EX527, a SIRT1-specific inhibitor, abrogated the cellular senescence induced by KD of BRG1. BRG1 KD cells resulted in smaller tumor formation than that in control cells in vivo. Collectively, our study shows that BRG1 has an important role in cellular senescence and tumor growth. The BRG1/SIRT1/p53 signal axis is a novel mechanism of cell senescence in CRC and is a new potential target for cancer therapy.
Introduction: MET mutations have been linked with highly progressive clinical behaviors and poor prognosis in several tumor types. Savolitinib (also known as AZD6094, HMPL-504 and volitinib) is a novel, potent, highly selective MET inhibitor and investigated in solid tumors. Methods: This is an open-label, single arm, multi-center phase II study to evaluate the efficacy and safety of savolitinib in MET exon 14 skipping mutant PSC or other types of NSCLC (NCT02897479). Eligible patients (pts) were diagnosed with unresectable or metastatic PSC or other types of NSCLC harboring MET exon 14 skipping mutations identified in tumor, plasma and/or pleural effusion. Mutations identified by local lab required to be confirmed by central lab test. Savolitinib 600mg was taken orally, once daily, until disease progression. The primary endpoint was objective response rate (ORR) per RECIST version 1.1. Here we report interim results after the first 34 enrolled pts. Results: As of 17 December 2018, 315 pts were prescreened or confirmed by central lab, 49 identified/confirmed with MET exon 14 skipping mutations, and 34 treated (14 PSC; 20 other types of NSCLC). Median age was 69 years (range 54-85) and 68% pts were male. Prior antitumor drugs for advanced disease: 17 pts were treatment naïve, 13 pts received 1 regimen, and 4 pts ≥2 regimens. According to investigators’ assessment of 31 patients, 12 pts had confirmed partial responses (PR); 4 pts with newly reported, yet to be confirmed PRs; 10 had stable disease; 2 had disease progression; and 3 pts were efficacy non-evaluable due to early discontinuation. The remaining 3 pts had not been evaluated yet. Tumor histology for the confirmed PR pts was as follows: 6 with PSC, 5 adenocarcinoma, 1 adenosquamous carcinoma. Median treatment duration for the confirmed PR pts was 34+ weeks (range: 16-96+ weeks). Among all 34 pts, the most common (≥20%) drug-related treatment emergent adverse events (TEAEs) were nausea (41%), edema peripheral (38%), alanine aminotransferase increased (32%), aspartate aminotransferase increased (29%) and vomiting (21%). Overall, 12 (35%) pts had ≥ grade 3 related TEAEs, and 5 (15%) pts discontinued treatment due to related TEAEs. The most common related TEAE leading to treatment discontinuation was drug-induced liver toxicity (6%). Five pts have died on-treatment: 3 unrelated/unlikely related AEs, 1 probably related to treatment (tumor lysis syndrome), and 1 primary cause unknown. Conclusion: Preliminary data suggested encouraging antitumor activity and an acceptable safety profile of savolitinib in pts with MET exon 14 mutated PSC or other types of NSCLC. Accrual of subjects in this study is ongoing. Citation Format: Shun Lu, Jian Fang, Lejie Cao, Xingya Li, Qisen Guo, Jianying Zhou, Ying Cheng, Liyan Jiang, Yuan Chen, Helong Zhang, Zongan Liang, Xin Zhang, Biao Wu, Jianhua Shi, Hua Xu, Jianjin Huang, Zhixiong Yang, Shan Zeng, Yanping Hu, Xiaodong Zhang, Jingxun Wu, Gongyan Chen, Nong Yang, Longzhen Zhang, Yinjia Fu, Jing Li, Linfang Wang, Yongxin Ren, Weiguo Su. Preliminary efficacy and safety results of savolitinib treating patients with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT031.
Phosphatidylinositol 3-kinase (PI3K) signaling plays an important role in the regulation of cellular lipid metabolism and non-alcoholic fatty liver disease (NAFLD). However, little is known about the role of the regulatory subunits of PI3K in lipid metabolism and NAFLD. In this study, we characterized the functional role of PIK3R3 in fasting-induced hepatic lipid metabolism. In this study, we showed that the overexpression of PIK3R3 promoted hepatic fatty acid oxidation via PIK3R3-induced expression of PPARα, thus improving the fatty liver phenotype in high-fat diet (HFD)-induced mice. By contrast, hepatic PIK3R3 knockout in normal mice led to increased hepatic TG levels. Our study also showed that PIK3R3-induced expression of PPARα was dependent on HNF4α. The novel PIK3R3-HNF4α-PPARα signaling axis plays a significant role in hepatic lipid metabolism. As the activation of PIK3R3 decreased hepatosteatosis, PIK3R3 can be considered a promising novel target for developing NAFLD and metabolic syndrome therapies.
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