Cancer Epigenetics

Investigators

• Epigenetics and genetics equally contribute to cancer pathogenesis.
• Epigenetics bridges the gap between human cancer and environmental exposure.
• Due to the promptness and reversibility, epigenetic modifications rapidly turn on cell fate determinators helping a subpopulation of cells escape drug-mediated killing.

Focus Areas

Role of the HIF1A-DNMT3A axis in AML1/ETO-driven acute myeloid leukemia

The fusion protein AML1/ETO (AE), resulting from the t(8;21) translocation, is one of the most common chromosomal abnormalities in acute myeloid leukemia (AML). It is a leukemia-initiating transcription factor, but the full-length AE itself is not leukemogenic in vivo. As AE-initiated transcription largely relies on AE protein complex in target promoters, multiple inhibitors targeting the individual components of the AE complex have been tested in AE positive (AE+) AML, but with relatively low success.

Hypoxia-inducible factor 1 (HIF1) is a key transcription factor in cancers and a well-studied oncogene. However, most previous studies focused on non-leukemic malignancies, and HIF1 was presumed to be mainly hypoxia-dependent factor in cancers. Dr. Liu's team is to test the hypothesis that HIF1 may promote AE leukemogenicity through enhancing AE transcriptional activities and modulating AE-governed DNA methylation landscape in AML cells; and that the gain-of-function of the AE-HIF1-DNMT3a axis may be a reliable molecular marker and vulnerable target, which defines patients with a poor prognosis in an otherwise prognostically favorable AE+ subgroup AML.

Role of RNA m6A aberrations in protein tyrosine kinase-targeted cancer therapy

Tyrosine kinase targeted (TKI) therapies have revolutionized leukemia treatment, but TKIs are not able to kill leukemia stem cells (LSCs), which are responsible for propagating and disease recurrence, and believed to be the source of treatment failure. The m6A is the most common internal modification in RNAs, including long non-coding RNAs (lncRNAs), and the fat mass and obesity-associated protein (FTO) is a major m6A demethylase. Further, the aberrant FTO-m6A axis has been found to significantly influence the development and progression of cancers, but with limited knowledge in drug resistance. lncRNA abnormalities are frequently associated with cancer disease progression and drug resistance.

However, whether and how m6A and lncRNAs coordinately regulate LSC fate in response to TKIs are unclear. Dr. Liu's team is interested in dissecting the role of the FTO-m6A-lncRNA cascade in regulating LSC persistence to TKIs and in exploring the therapeutic potential to pharmacologically target the FTO-m6A-lncRNA cascade for overriding persistent LSCs.

The development of nanovehicles (RNA nanoparticles, exosomes) to deliver siRNAs/small molecule inhibitors to overcome resistance to molecular-targeted therapies.

While the initial responses are seen in molecular-targeted therapies, many patients who respond initially experience relapse and disease recurrence, representing a major hurdle for successful cancer treatment. Further, off-target uptake and low efficient delivery of therapeutic agents (e.g., small molecule inhibitors and RNA oligos) lead to unwanted adverse effects in vivo, especially in leukemia therapy, where few targets are available to guide drug delivery.

A promising approach to these problems would be the use of novel nanocarriers (e.g., RNA nanoparticles) and new cell surface markers for targeted delivery of new therapeutic agents to resistant leukemia cells. Dr. Liu’s team is to i) develop novel RNA nanoparticles conjugated with RNA aptamer of surface markers (e.g., CD133; highly expressed in resistant cells) to specifically deliver TKI resistant genes (e.g., FTO, the fat mass and obesity-associated protein) siRNAs for eradicating resistant cells, and ii) decipher the molecular mechanisms underlying the anticancer activities of RNA nanoparticles.

Selected Publications

Dou L, Yan F, Pang J, Zheng D, Li D, Gao L, Wang L, Xu Y, Shi J, Wang Q, Zhou L, Shen N, Singh P, Wang L, Li Y, Gao Y, Liu T, Chen C, Al-Kali A, Litzow M, Chi Y, Bode A, Liu C, Huang H, Liu D, Marcucci G, Liu S,* Yu L. Protein Lysine 43 Methylation by EZH1 Promotes AML1-ETO Transcriptional Repression in Leukemia. Nature Communications. 2019 (accepted). (*Corresponding author and Lead contact).

Yan F, Al-Kali A, Zhang Z, Liu J, Pang J, Zhao N, He C, Litzow M, Liu S. A dynamic N6-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors. Cell Research. 2018 Nov;28(11):1062-1076.

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 May 1;78(9):2343-2355. *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.

*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)

Bibliography

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