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OUR WORK

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The research in our lab centers on the multi-functional transcription factor nuclear factor κB (NF-κB). As a hallmark in many cancers and a key link between inflammation and cancer, the pivotal transcription factor NF-κB is a “hot” target for disease treatment. My research focuses on addressing how NF-κB is regulated and how this regulation contributes to tumorigenesis. Ultimately, these studies may provide a rational basis for the design of new strategies for treating NF-κB-activated cancers and inflammatory disorders.

C7MB00391A_OFC.jpg

Fig. 1. Protein Arginine Methyltransferase 5

Fig. 2. F-box leucine repeat rich protein 11 (FBXL11)

Epigenetic Regulation of NF-kB

in cancer and inflammatory disease

We have discovered that the histone modifying enzymes, such as protein arginine methyltransferase 5 (PRMT5) (ref. 1, 2) (Fig 1) and the F-box leucine repeat rich protein 11 (FBXL11) (ref. 2-4) (Fig 2), a known histone H3 lysine 36 (H3K36) demethylase are novel regulators of NF-κB. Currently, we are studying the role of these histone modifying enzymes in cancer. Specifically, we have adapted the AlphaLISA technique into a high throughput screen (HTS) platform to identify PRMT5 small molecule inhibitors. This work has resulted in an International Patent Application (5) regarding “Small molecule protein arginine methyltransferase 5 (PRMT5) inhibitors and methods of treatment”. The lead compound and its derivatives may serve as the basis for new medicine development to combat cancer, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and breast cancer (BC) (6, 7).  

 

Furthermore, since elevated NF-κB activity has been widely observed in both chronic inflammatory bowel disease (IBD) and colitis-associated colon cancer (CAC), and is believed to be a key link between IBD and CAC, therefore, NF-κB is widely considered to be an attractive therapeutic target for CAC. We have successfully established genetically engineered mouse models to investigate the role of FBXL11 in CAC and other inflammation related diseases, such as diabetes and atherosclerosis.

VBIM.jpg

Using Validation-based insertional mutagenesis (VBIM) technique to discover novel genes

Fig. 3. Principle of VBIM lentiviral vectors. A. VBIM vectors have LoxP sites on both ends of the vector (left). A gene in the genome is randomly represented (right). The cell phenotype is wild type. B. After VBIM virus infection, the VBIM vectors will randomly insert into the genome, form a hybrid with the affected gene, changing the cell from wild type to mutant phenotype. C. In order to verify whether this insertion event is the cause of the change of the cell phenotype, Cre recombinase will be used to excise the vector (from LoxP sites on both ends). The inserted gene will be reversed back to the original gene with a very small footprint left from the VBIM vector, which will NOT affect the gene property. Therefore, the cell phenotype will be reversed from mutant phenotype to wild type. If this is the case, we have proven that this mutant is a reversible mutant, and the VBIM insertion event is the cause of the change of the cell phenotype (3, 8).

VBIM (Fig 3) is a powerful genetic approach for gene discovery (3, 8). We have employed this innovative approach to identify novel regulators of NF-κB. These regulators may have great potential to serve as new biomarkers and therapeutic targets for cancer. Furthermore, understanding the underlying molecular mechanisms regarding how these novel regulators control NF-κB activity may help to devise innovative therapeutic strategies to control NF-κB activity in cancer.

 

Additionally, our lab is also utilizing VBIM technique to discover carboplatin and paclitaxel resistance genes in cancer. Once identified, targeting these genes may help to overcome chemoresistance to carboplatin or paclitaxel, thus, improving their efficacies for cancer treatment. Finally, discovery of novel drug resistance genes may help physicians to design more precise treatment to each individual cancer patient.

 

In conclusion, the research in our lab utilizes a broad range of advanced research techniques and experimental models to discover novel aspects of NF-κB regulation and new genes for drug resistance, with the hope of identifying innovative biomarkers, therapeutic targets in cancer and other NF-κB related diseases, and ultimately, lead to the development of new medicines to treat these devastating diseases.

Citations:

  1. Wei H, Wang B, Miyagi M, She Y, Gopalan B, Huang D, Ghosh G, Stark GR, Lu T. (2013). PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB. Proc Natl Acad Sci U S A. 110(33): 13516–13521. Published online 2013 Jul 31. doi: 10.1073/pnas.1311784110-Selected for F1000 Prime

  2. Lu T and Stark GR. (2015). NF-κB: Regulation by Methylation. Cancer Res. 75(18):3692-5. doi: 10.1158/0008-5472.CAN-15-1022. PubMed PMID: 26337909; PubMed Central PMCID: PMC4573795.

  3. Lu T, Jackson MW, Singhi AD, Kandel ES, Yang M, Zhang Y, Gudkov AV, Stark GR. (2009). Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NF-kB. Proc Natl Acad Sci U S A. 106(38):16339-44. doi: 10.1073/pnas.0908560106. PubMed PMID: 19805303; PubMed Central PMCID: PMC2736141.

  4. Lu T, Jackson MW, Wang B, Yang M, Chance MR, Miyagi M, Gudkov AV, Stark GR. (2010). Regulation of NF-kB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci U S A. 107(1):46-51. doi: 10.1073/pnas.0912493107. PubMed PMID: 20080798; PubMed Central PMCID: PMC2806709.

  5. Lu T and Prabhu L. Small molecule protein arginine methyltransferase 5 (PRMT5) inhibitors and methods of treatment. International Patent Application, PCT/US2017/058572 filed on Oct. 26, 2017

  6. Prabhu L, Wei H, Chen L, Demir Ö, Sandusky G, Sun E, Wang J, Mo J, Zeng L, Fishel M, Safa A, Amaro R, Korc M, Zhang ZY, Lu T. (2017). Adapting AlphaLISA high throughput screen to discover a novel small-molecule inhibitor targeting protein arginine methyltransferase 5 in pancreatic and colorectal cancers. Oncotarget . 8(25):39963-39977. doi: 10.18632/oncotarget.18102. PubMed PMID: 28591716; PubMed Central PMCID: PMC5522311.-Selected as Cover page.

  7. Prabhu L, Chen L, Wei H, Demir Ö, Safa A, Zeng L, Amaro RE, O'Neil BH, Zhang ZY, Lu T. (2017). Development of an AlphaLISA high throughput technique to screen for small molecule inhibitors targeting protein arginine methyltransferases. Mol Biosyst. 13(12):2509-2520. doi: 10.1039/c7mb00391a. PMID: 29099132 – Selected as Cover Page.

  8. Lu T and Stark GR. (2010). Use of forward genetics to discover novel regulators of NF-kB. Cold Spring Harb Perspect Biol. 2(6):a001966. doi: 10.1101/cshperspect.a001966. PubMed PMID: 20516132; PubMed Central PMCID: PMC2869522.

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