Apeutic agents by affecting their apoptotic potential [11]. In addition, we have shown that autophagy activated by hypoxia mediates the tolerance of hepatocellular carcinoma cells to nutrient deprivation, which is dependent on the activity of Beclin 1 [19]. Wang, et al. found that PADI4 regulates the mTORC1 signaling pathway and PADI inhibitors are potential anticancerFan et al. Cell Bioscience 2014, 4:49 http://www.cellandbioscience.com/content/4/1/Page 9 ofreagents that activate tumor suppressor gene expression alone or in combination with HDAC inhibitors [31]. Interestingly, our study indicated that HCC cells with overexpressed PADI4 were observed to undergo autophagy, which is known as a protective mechanism for cells to resist the cell toxicity from chemotherapy. Autophagy inhibitor could effectively restore the sensitivity of HCC cells to chemotherapy in vitro and in vivo. These results indicate that PADI4 could induce chemoresistance in HCC cells by leading autophagy.and interpretation, final approval of manuscript. All authors read and approved the final manuscript. Acknowledgements This study was supported by the Natural Science Foundation of China (Grant No: 81372212, 81373203), Shanghai Municipal Science and Technology Commission (No. 12XD1404300, No.11DZ1973802), the Natural Science Foundation of Jiangsu Province (No. BK2011251, BL2013012). Author details 1 Department of Clinical Laboratory, Shanghai East Hospital, Tongji University Medical School, No. 150, Jimo Road, Shanghai 200120, China. 2Clinical Oncology Laboratory, Changzhou cancer Hospital of Soochow University, Changzhou 213001, China. 3Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China. Received: 9 April 2014 Accepted: 7 August 2014 Published: 26 August 2014 References 1. Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ: PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays 2003, 25(11):1106?118. 2. Gyorgy B, Toth E, Tarcsa E, Falus A, Buzas EI: Citrullination: a posttranslational modification in health and disease. Int J Biochem Cell Biol 2006, 38(10):1662?677. 3. Darrah E, Rosen A, Giles JT, Andrade F: Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: novel insights into autoantigen selection in rheumatoid arthritis. Ann Rheum Dis 2012, 71(1):92?8. 4. Chang X, Hou X, Pan J, Fang K, Wang L, Han J: Investigating the pathogenic role of PADI4 in oesophageal cancer. Int J Biol Sci 2011, 7(6):769?81. 5. Wang L, Chang X, Yuan G, Zhao Y, Wang P: Expression of peptidylarginine deiminase type 4 in ovarian tumors. Int J Biol Sci 2010, 6(5):454?64. 6. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Chaetocin msds Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K: Functional haplotypes of PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28404814 PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003, 34(4):395?02. 7. Chang X, Han J: Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors. Mol Carcinog 2006, 45(3):183?96. 8. Chang X, Fang K: PADI4 and tumourigenesis. Cancer Cell Int 2010, 10:7. 9. Zhang C, Fan L, Fan T, Wu D, Gao L, Ling Y, Zhu J, Li R, Wei L: Decreased PADI4 mRNA a.