Shujun Liu, Ph.D.
Associate Professor
Section Leader
Cancer Epigenetics & Experimental Therapeutics

Dr. Shujun Liu - The Hormel Institute


• Epigenetics and genetics equally contribute to tumorigenesis;
• Epigenetics bridges the gap between human cancer and environmental exposure;
• Due to the promptness and reversibility, epigenetic modifications rapidly turn on cell fate determinators facilitating cancer cell evolved through drug selection.

1. Discover FABP4-IL-6-DNMT1 cascade as a hitherto unknown molecular link between obesity and cancer

Cancer is the representatively systemic lesions taking over the first place of lethal diseases throughout the world. Obesity, a chronic disease, is an important risk factor for many types of human illnesses. The World Health Organization estimates that one-quarter of the world’s population are obese. While it is a well-established concept that obesity is strongly associated with an increased incidence of breast cancer, colon cancer, pancreatic cancer and prostate cancer etc., whether and how obesity contributes to leukemia remain unexplored. Our findings reveal that dietary-induced obesity mediates aggressive leukemia growth in vitro and in vivo, thus, for the first time, experimentally demonstrating obesity-leukemia association. We present compelling evidence that a family of fatty acid binding proteins (FABPs) is responsible for the aggressive leukemic phenotypes in obesity, because a single change of FABP4 in host or in leukemia cells is sufficient to alter leukemia cell fate. Mechanistically, the obese environment educates leukemia cells via FABP4 overproduction followed by DNMT1 upregulation, DNA hypermethylation and further silencing of tumor suppressor genes. Theoretically, our findings identify FABP4 as an entirely new type of epigenetic modulator, in line with other members, such as TET (ten-eleven-translocation) proteins, cytidine deaminases or IDH (isocitrate dehydrogenase) mutations. Our discoveries unravel FABP4-IL-6-DNMT1 cascade as a novel molecular rule behind obesity-cancer association. In terms of practical use, our findings open a novel window of targeting FABP4/DNMT1 axis for treating leukemia, and, potentially, other types of cancer.

2. Discover fusion proteins as epigenetic modulators through multiple mechanisms

The oncogenic fusion proteins (e.g., AML1/ETO), resulting from chromosomal translocations [e.g., t(8;21)], are leukemia-initiating transcription factors, and tightly associated with aberrant DNA methylation signature that predicts worse outcomes. Although we were the first to show that AML1/ETO recruits DNMT1 to repress AML1 target genes in leukemia, these findings are insufficient to explain why the promotors of many genes without AML1/ETO binding elements are hypermethylated. Recently, we identified a positive feedback loop, AML1/ETO-HIF1α, which binds to DNMT3a promoter and upregulates DNMT3a expression leading to an increase of global and gene specific DNA methylation. These findings provide additional mechanisms behind AML1/ETO-driven DNA hypermethylation, supporting that fusion proteins modify epigenetic landscapes in leukemia cells through both transcriptional and posttranscriptional regulations of DNMTs.

Shujun Liu - The Hormel Institute

From left to right: Shujun Liu, Fei Yan, Liping Dou, Na Zhao, Emily Johannsen, Jiuxia Pang

3. Protein kinases and DNA methyltransferases cooperatively mediate drug resistance

Since aberrant DNA methylation and abnormal KIT function critically contribute to cancer pathogenesis, as independent practice, KIT and DNMT1 have been extensively used for therapeutic targets and their inhibitors have been tested in various pre- and clinical models. However, resistance of tumor cells to kinase inhibitors or DNA hypomethylating agents poses huge limitations to their use in treatment. Our findings suggest that resistance to decitabine and PKC412 eventually results from simultaneously re-methylated DNA and re-activated kinase cascades, as evidenced by the upregulation of DNMT1, DNMT3a, DNMT3b and tyrosine-protein kinase KIT, the enhanced phosphorylation of KIT and its downstream effectors as well as the increased global and gene-specific DNA methylation with further silencing of tumor suppressor genes. Interestingly, the resistant cells had higher capability of colony-formation and wound-healing than parental cells in vitro, with stronger tumorigenic potential in vivo. In addition, we recently showed that resistance to cisplatin in small cell lung cancer takes place through a new signaling network, DNMT1-KIT-PD1. Theoretically, our findings shed light on the molecular biology of drug resistance; practicably, our studies provide a sound rationale in clinical trials for using inhibitors of new signaling network to override drug resistant phenotypes, and also identify new opportunities for early therapeutic intervention against the emergence of drug-resistance.

4. Identify multiple new epigenetic modulators in cancers

Aberrant epigenetics is a hallmark of cancer, but the critical regulators controlling DNA methylation machinery are largely unknown. Our findings revealed that a) fusion proteins resulting from chromosomal translations initiate aberrant epigenetics through transcriptional and posttranscriptional regulation of DNMTs; b) the environmental factors reform the epigenetic landscapes via NFkB/IL-6/STAT3 signaling in AML cells; c) the deregulated microRNAs (e.g., miR-29b, miR-101) shape DNA methylation patterns through targeting the 3’ UTR of DNMT mRNA; d) nucleolin regulates DNA methylation signatures by the hyperactive NFkB pathway in leukemia; e) receptor tyrosine kinases function as hitherto unknown epigenetic modulators. We have for the first time demonstrated that all these regulators are showing promise in developing novel DNA hypomethylating agents.

Selected Publications

Hao J, Yan F, Zhang Y, Triplett A, Zhang Y, Schultz D, Sun Y, Zeng J, Silverstein K, Zheng Q, Bernlohr D, Cleary M, Egilmez N, Sauter E, Liu S*, Suttles J*, Li B*.  Expression of adipocyte/ macrophage fatty acid binding protein in tumor associated macrophages promotes breast cancer progression. Cancer Research. 2018 (Accepted; *Corresponding Author)

Yan F, Shen N, Pang J, Zhao N, Zhang Y, Bode A, Al-Kali A, Litzow M, Li B, Liu S. A Vicious Loop of Fatty Acid-Binding Protein 4 and DNA Methyltransferase 1 Promotes Acute Myeloid Leukemia and Acts as a Therapeutic Target. Leukemia. 2017 Oct 10.

Yan F, Shen N, Pang J, Zhao N, Deng B, Li B, Yang Y, Yang P, Molina J, Liu S. A Regulatory Circuit Composed of DNA Methyltransferases and Receptor Tyrosine Kinases Controls Lung Cancer Cell Aggressiveness. Oncogene. 2017 Dec 14;36(50):6919-6928.

Shen N, Yan F, Pang J, Zhao N, Gangat N, Wu L, Bode A, Al-Kali A, Litzow M, Liu S. Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia. Clinical Cancer Research. 2017 Oct 15;23(20):6254-6266. (Cover Article)

Yan F, Shen N, Pang J, Zhang Y, Rao E, Bode A, Al-Kali A, Zhang D, Litzow M, Li B, Liu S. Fatty Acid Binding Protein FABP4 Mechanistically Links Obesity with Aggressive AML by Enhancing Aberrant DNA Methylation in AML Cells. Leukemia. 2017 Jun;31(6):1434-1442.

Yan F, Pang J, Peng Y, Molina J, Yang P, Liu S. Elevated Cellular PD1/PD-L1 Expression Confers Acquired Resistance to Cisplatin in Small Cell Lung Cancer Cells. PLoS One. 2016 Sep 9;11(9):e0162925. (Featured in PLOS journal and included in the PLOS Editor’s Picks Collection, Cancer Immunotherapy)

Gao X, Yan F, Lin J, Gao L, Lu X, Wei S, Shen N, Pang J, Ning Q, Komeno Y, Deng A, Xu Y, Shi J, Li Y, Zhang D, Nervi C, *Liu S, Yu L. AML1/ETO Cooperates with HIF1α to Promote Leukemogenesis through DNMT3a Transactivation. Leukemia. 2015 Aug;29(8):1730-40. (*Corresponding Author/Lead Contact)

Liu S. Epigenetics Advancing Personalized Nanomedicine in Cancer Therapy. Advanced Drug Delivery Reviews. 2012 Oct;64(13):1532-43.

Mishra A, Liu S, Santhanam R, Deanna S, Jackie J, Yang X, Wu L, Chandler J, Wu, Y, Heerema N, Chan K, Perrotti D, Zhang J, Pierluigi P, Garzon R, Racke F, Hickey C, Lee R, Marcucci G, Caligiuri M. Aberrant Overexpression of IL-15 Initiates Large Granular Lymphocyte Leukemia through Chromosomal Instability and DNA Hypermethylation. Cancer Cell. 2012 Nov 13;22(5):645-55.

*Liu S, Wu L, Pang J, Santhanam R, Schwind S, Wu Y, Hickey C, Yu J, Becker H, Maharry K, Radmacher M, Li CL, Whitman S, Eiring A, Briesewitz R, Caligiuri M, Byrd J, Croce C, Bloomfield C, Perrotti D, Garzon R, *Marcucci G. Sp1/NFkB/HDAC/miR-29b Regulatory Network in KIT-driven Myeloid Leukemia. Cancer Cell. 2010 Apr 13;17(4):333-47. (*Corresponding Author)


Complete List of Published Work in MyBibliography