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// Xiayang Xie 1, 2 , Shou-Ching Tang 3, 4 , Yafei Cai 3 , Wenhu Pi 3 , Libin Deng 3 , Guangyu Wu 5 , Alain Chavanieu 6 , Yong Teng 1, 3, 7 1 Department of Oral Biology, Augusta University, Augusta, GA, USA 2 Department of Pediatrics, Emory Children’s Center, Emory University, Atlanta, GA, USA 3 Georgia Cancer Center, Augusta University, Augusta, GA, USA 4 Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China 5 Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, USA 6 Institut des Biomolecules Max Mousseron (IBMM), UMR 5247, Universite de Montpellier, CNRS, ENSCM, France 7 Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA Correspondence to: Yong Teng, email: yteng@augusta.edu Keywords: ARF1, breast cancer, metastasis, LM11, zebrafish Received: June 14, 2016 Accepted: August 05, 2016 Published: August 10, 2016 ABSTRACT Metastasis is the major cause of cancer-related death in breast cancer patients, which is controlled by specific sets of genes. Targeting these genes may provide a means to delay cancer progression and allow local treatment to be more effective. We report for the first time that ADP-ribosylation factor 1 ( ARF1 ) is the most amplified gene in ARF gene family in breast cancer, and high-level amplification of ARF1 is associated with increased mRNA expression and poor outcomes of patients with breast cancer. Knockdown of ARF1 leads to significant suppression of migration and invasion in breast cancer cells. Using the orthotopic xenograft model in NSG mice, we demonstrate that loss of ARF1 expression in breast cancer cells inhibits pulmonary metastasis. The zebrafish-metastasis model confirms that the ARF1 gene depletion suppresses breast cancer cells to metastatic disseminate throughout fish body, indicating that ARF1 is a very compelling target to limit metastasis. ARF1 function largely dependents on its activation and LM11, a cell-active inhibitor that specifically inhibits ARF1 activation through targeting the ARF1-GDP/ARNO complex at the Golgi, significantly impairs metastatic capability of breast cancer cell in zebrafish. These findings underline the importance of ARF1 in promoting metastasis and suggest that LM11 that inhibits ARF1 activation may represent a potential therapeutic approach to prevent or treat breast cancer metastasis.

// Chao Shi 1 , Dengliang Huang 1 , Nonghua Lu 2 , Dan Chen 1 , Minhong Zhang 1 , Yehong Yan 3 , Libin Deng 4 , Quqin Lu 5 , Hua Lu 6 , Shiwen Luo 1 1 Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China 2 Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China 3 Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China 4 Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, China 5 Department of Epidemiology and Biostatistics, School of Public Health, Nanchang University, Nanchang, Jiangxi, China 6 Department of Biochemistry and Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA Correspondence to: Shiwen Luo, email: shiwenluo@ncu.edu.cn Keywords: glioma-associated oncogene 2, Forkhead box M1, kinesin family member 20A, transcriptional regulation, hepatocellular carcinoma Received: January 29, 2016 Accepted: March 14, 2016 Published: March 28, 2016 ABSTRACT Glioma-associated oncogene 2 (Gli2), a primary transcriptional regulator of Hedgehog (Hh) signaling, is essential for hepatocellular carcinoma (HCC) growth and survival. However, the underlying molecular mechanism and crucial downstream targets of Gli2 in human HCC are not fully understood. Here, we report the identification of kinesin family member 20A (KIF20A) as a novel downstream target of Gli2, which is important for HCC proliferation and tumor growth. Inhibition of Hh signaling leads to a remarkable decrease of KIF20A expression in HCC cells, whereas overexpression of Gli2 elevates KIF20A expression by activating Forkhead Box M1 (FoxM1)-MMB complex-mediated transcription of this kinesin gene. Gli2-induced HCC cell growth requires enhanced expression of KIF20A, and knockdown of Gli2 or KIF20A represses the proliferation of HCC cells in vitro and in vivo . Correlated with these results, analyses of clinical HCC samples show that Gli2, FoxM1 and KIF20A are highly elevated in primary HCC samples and represent significant risk factors for HCC recurrence and survival. Conclusion: KIF20A is an important downstream target gene of Hh signaling. And, the Gli2-KIF20A axis is essential for the proliferation and growth of human HCC cells. Our study also suggests Gli2-KIF20A axis as a potential target for future therapeutic intervention and as an independent prognostic biomarker for HCC.

Immunosuppression is a prevalent clinical feature in chronic lymphocytic leukemia (CLL) patients, with many patients demonstrating increased susceptibility to infections as well as increased failure of an antitumor immune response. However, much is currently not understood regarding the precise mechanisms that attribute to this immunosuppressive phenotype in CLL. To provide further clarity to this particular phenomenon, we analyzed the T-cell profile of CLL patient samples within a large cohort and observed that patients with an inverted CD4/CD8 ratio had a shorter time to first treatment as well as overall survival. These observations coincided with higher expression of the immune checkpoint receptor PD-1 in CLL patient CD8+ T cells when compared to age-matched healthy donors. Interestingly, we discovered that increased PD-1 expression in CD8+ T cells corresponds with decreased DNA methylation levels in a distal upstream locus of the PD-1 gene PDCD1. Further analysis using luciferase reporter assays suggests that the identified PDCD1 distal upstream region acts as an enhancer for PDCD1 transcription and this region becomes demethylated during activation of naive CD8+ T cells by anti-CD3/anti-CD28 antibodies and IL2. Finally, we conducted a genome-wide DNA methylation analysis comparing CD8+ T cells from CLL patients against healthy donors and identified additional differentially methylated genes with known immune regulatory functions including CCR6 and KLRG1. Taken together, our findings reveal the occurrence of epigenetic reprogramming taking place within CLL patient CD8+ T cells and highlight the potential mechanism of how immunosuppression is accomplished in CLL.