Tumor‐associated macrophages (TAMs) are one of the most abundant immunosuppressive cells in the tumor microenvironment and possess crucial functions in facilitating tumor progression. Emerging evidence indicates that altered metabolic properties in cancer cells support the tumorigenic functions of TAMs. However, the mechanisms and mediators the underly the cross‐talk between cancer cells and TAMs remain largely unknown. In the present study, we revealed that high solute carrier family 3 member 2 (SLC3A2) expression in lung cancer patients was associated with TAMs and poor prognosis. Knockdown of SLC3A2 in lung adenocarcinoma cells impaired M2 polarization of macrophages in a coculture system. Using metabolome analysis, we identified that SLC3A2 knockdown altered the metabolism of lung cancer cells and changed multiple metabolites, including arachidonic acid, in the tumor microenvironment. More importantly, we showed that arachidonic acid was responsible for SLC3A2‐mediated macrophage polarization in the tumor microenvironment to differentiate into M2 type both in vitro and in vivo. Our data illustrate previously undescribed mechanisms responsible for TAM polarization and suggest that SLC3A2 acts as a metabolic switch on lung adenocarcinoma cells to induce macrophage phenotypic reprogramming through arachidonic acid.

Abnormal activation of the oncogene YAP in the Hippo pathway is a major feature in liver cancer and inactivation of MST1/2 has been shown to be responsible for the overactivation of YAP that led to tumorigenesis. However, mechanisms underlying MST1/2 dysregulation remain poorly understood. RNA‐seq analysis and genome (KEGG) pathway enrichment analysis were used to identify genes and pathways that were regulated by SIRT7. qRT‐PCR, ChIP, and luciferase assay were used to investigate transcriptional regulation. Mass spectrometry, co‐immunoprecipitation and immunoprecipitation were used to exam protein–protein interaction and post‐transcriptional modification. A xenograft mouse model was used to confirm the effect of SIRT7 and SIRT7 inhibitors on hepatocellular carcinoma (HCC) proliferation in vivo. We found that SIRT7 suppresses MST1 by both transcriptional regulation and post‐transcriptional modification, which in turn promotes YAP nuclear localization and transcriptional activation in liver cancer. Mechanistically, we revealed that SIRT7 suppresses MST1 transcription by binding to the MST1 promoter and inducing H3K18 deacetylation in its promoter region. In addition, SIRT7 directly binds to and deacetylates MST1, which primes acetylation‐dependent MST1 ubiquitination and protein degradation. In clinical samples, we confirmed a negative correlation between SIRT7 and MST1 protein levels, and high SIRT7 expression correlated with elevated YAP expression and nuclear localization. In addition, SIRT7 specific inhibitor 2800Z sufficiently inhibited HCC growth by disrupting the SIRT7/MST1/YAP axis. Our data thus revealed the previously undescribed function of SIRT7 in regulating the Hippo pathway in HCC and further proved that targeting SIRT7 might provide novel therapeutic options for the treatment of liver cancer.

Optimal therapeutic strategies for liver cancer patients remain challenging due to the high recurrence rate after surgical resection and chemotherapy resistance. Emerging evidence has shown that epigenetic factor SIRT7 is involved in various aspects of cancer biology, while inactive SIRT7 reverses human cancer phenotype and suppresses tumor growth. In the present study, we predicted the SIRT7 structure by using the fold recognition (or threading) method and performed structure-based virtual screening to develop specific SIRT7 inhibitor by docking 939319 structurally diverse compounds with SIRT proteins. Compounds with high affinities to SIRT7 but low affinities to other SIRT proteins were chosen as candidates of specific SIRT7 inhibitor. Our leading compounds 2800Z and 40569Z showed strong interaction with SIRT7 protein, and specifically inhibited SIRT7 deacetylation activity in vitro. Our docking results also revealed that ARG-120, TRP-126, and HIS-187 were critical sites responsible for interaction of SIRT7 with small molecules. Mutations in the aforementioned sites significantly abolished interaction and inhibitory effects of compounds to SIRT7. In addition, in vivo data indicated that compounds 2800Z and 40569Z were able to induce apoptosis and increase chemosensitivity to sorafenib in human liver cancer. Our findings demonstrated targeting SIRT7 may offer novel therapeutic options for cancer management, and the value of compounds 2800Z and 40569Z as chemical probes for the study of SIRT7 biological functions as well as starting leads for the development of new therapeutic options against liver cancer.

Irinotecan is the first line chemotherapy drug used for treatment of metastatic colorectal cancer worldwide. There is increasing evidence suggesting that liver damage, including steatosis and steatohepatitis, can be caused during the treatment involving irinotecan. However, molecular mechanisms by which irinotecan-induced liver injury remain elusive. In this study, we found that irinotecan treatment caused significant elevation of ALT, inflammation, and fat accumulation in the liver, which are associated with hepatic macrophage activation. Depletion of macrophages by clodronate liposome improved irinotecan induced liver injury and inflammatory response in mice. In vitro data indicated that irinotecan induced intracellular ROS production in primary hepatocyte and upregulating of toll-like receptor (TLRs) family expression in macrophages. Supernatant from irinotecan treated hepatocyte triggered macrophage activation and upregulation of TLRs in macrophage, and N-acetylcysteine (NAC) abolished these effects. By using co-culture system, we further revealed that irinotecan activated macrophage induced impairment of lipid metabolism and promoted apoptosis in hepatocyte and NAC prevented macrophage-induced cell death and partially revered impaired lipid metabolism in hepatocytes. By using the irinotecan liver injury model, we demonstrated that combining NAC with irinotecan prevented irinotecan-induced macrophage activation, TLR upregulation, liver injury, and partially prevented the accumulation of triglycerides in liver. Our results thus indicated that macrophages play a critical role in irinotecan-induced liver injury, and targeting ROS provides new options for development of hepatoprotective drugs in clinical practice.

NRF2 has been recognized as a central hub that neutralizes ROS and restores intracellular redox balance. In addition to KEAP1 mediated ubiquitin-proteasome degradation, post-translational modifications of NRF2 are critical for regulating its nuclear translocation and activation but precise mechanisms underly this regulation remain elusive. In this study, we found that SIRT7 was sufficient and essential for NRF2 nuclear localization and activation. Knockdown of SIRT7 significantly impaired intercellular ROS homeostasis and increased apoptosis in response to oxidative stress including chemodrug treatment. SIRT7 interacted with NRF2 and induced its deacetylation, by which inhibited binding of NRF2 to KEAP1, enhanced NRF2 protein stability and promoted its nuclear translocation. SIRT7 induced NRF2 deacetylation at K443 and K518 sites. Lysine-arginine mutations of these sites (2KR NRF2) significantly reduced KEAP1/NRF2 binding, increased NRF2 nuclear translocation and target gene expression, decreased intercellular ROS level, whereas lysine-glutamine (2KQ) mutant showed similar subcellular localization and functions with WT. Knockdown SIRT7 in hepatocyte exacerbated Oxaliplatin (Oxa) induced hepatic injury and inflammation. While AAV8-NRF2-mediated hepatic NRF2 overexpression or NRF2 agonist significantly prevented Oxa-induced elevation of ALT levels, sinusoidal dilatation and inflammation in SIRT7 ^HKO mice. Our data thus uncovered previously unidentified role of SIRT7 in modulating NRF2 nuclear localization and activation via deacetylation. Activating SIRT7 might offer protection against chemodrug-induced liver injury.