Lu Laboratory

Research in the Lu Laboratory 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. The research of Tao Lu, PhD, 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.

Active Research

Research in the Lu 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.

Epigenetic Regulation of NF-kB in cancer and inflammatory disease

The lab has discovered that the histone modifying enzymes, such as protein arginine methyltransferase 5 (PRMT5) (ref. 1, 2) and the F-box leucine repeat rich protein 11 (FBXL11) (ref. 2-4), a known histone H3 lysine 36 (H3K36) demethylase are novel regulators of NF-κB. Currently, these researchers 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. The lab team has successfully established genetically engineered mouse models to investigate the role of FBXL11 in CAC and other inflammation related diseases, such as diabetes and atherosclerosis.

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

VBIM 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, the Lu Lab is 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.

Citations

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

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.

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.

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.

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

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.

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.

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.

Current Research Funding

NIH NIGMS
#1R01 GM120156-01A1
09/2017-08/2022
Role: PI

Project Title: Gene-specific responses to NF-kB through lysine and arginine methylation of p65
Overlap: NONE

NIH NIGMS
#1R01 GM120156-01A1
09/2017-08/2022
Role: PI

Project Title: Gene-specific responses to NF-kB through lysine and arginine methylation of p65
Overlap: NONE

100 Voices of Hope Hunch Grant
#2987613
06/2017-12/2018
Role: PI

Project Title: A novel approach to discover drug resistance genes in metastasized cancer cells.

Selected 10 Publications

A complete list of published work can be found on the National Center for Biotechnology Information website.

Prabhu L, Chen L, Wei H, Demir Ö, Safa A, Zeng L, Amaro RE, O’Neil BH, Zhang ZY, Lu T. Development of an AlphaLISA high throughput technique to screen for small molecule inhibitors targeting protein arginine methyltransferases.  BioSyst.2017; 13(12):2509-2520. NIHMSID: NIHMS917805 PubMed [journal] PMID: 29099132, PMCID: PMC5759323 Featured on Cover Page

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. Adapting AlphaLISA high throughput screen to discover a novel small-molecule inhibitor targeting protein arginine methyltransferase 5 in pancreatic and colorectal cancers. Oncotarget. 2017; 8(25):39963-39977. PubMed [journal] PMID: 28591716, PMCID: PMC5522311 -1) Featured on front cover, Priority Paper, 2) Honorable Mention Award, Cancer Research Day, 3) Honorable Mention, Erica M. Daniel Kepner Award for Scientific Achievemen

Martin M, Hua L, Wang B, Wei H, Prabhu L, Hartley AV, Jiang G, Liu Y, Lu T. Novel Serine 176 Phosphorylation of YBX1 Activates NF-κB in Colon Cancer. J Biol. Chem.2017; 292(8):3433-3444. PubMed [journal] PMID: 28077578, PMCID: PMC5336175

Prabhu L, Mundade R, Wang B, Wei H, Hartley AV, Martin M, McElyea K, Temm CJ, Sandusky G, Liu Y, Lu T. Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer. 2015; 6(30):29396-412. PubMed [journal] PMID: 26318844, PMCID: PMC4745735

Lu T, Stark GR. NF-κB: Regulation by Methylation. Cancer Res. 2015; 75(18):3692-5. NIHMSID: NIHMS696108 PubMed [journal] PMID: 26337909, PMCID: PMC4573795

Wang B, Wei H, Prabhu L, Zhao W, Martin M, Hartley AV, Lu T. Role of Novel Serine 316 Phosphorylation of the p65 Subunit of NF-κB in Differential Gene Regulation. J Biol. Chem.2015; 290(33):20336-47. PubMed [journal] PMID: 26082493, PMCID: PMC4536440 –Selected for Donald Bowman Award

Lu T, Yang M, Huang DB, Wei H, Ozer GH, Ghosh G, Stark GR. Role of lysine methylation of NF-κB in differential gene regulation. Nat. Acad. Sci. USA. 2013; 110(33):13510-5. PubMed [journal] PMID: 23904479, PMCID: PMC3746872 F1000 Prime highlighted paper

Wei H, Wang B, Miyagi M, She Y, Gopalan B, Huang DB, Ghosh G, Stark GR, Lu T. PRMT5 dimethylates R30 of the p65 subunit to activate NF-κB.  Nat. Acad. Sci. USA. 2013; 110(33):13516-21. PubMed [journal] PMID: 23904475, PMCID: PMC3746871-1) Selected for F1000 Prime, 2) Hal Broxymeyer & Victoria Champion Outstanding Publication Award, 3) 2nd Place Award, Cancer Research Day

Lu T, Jackson MW, Wang B, Yang M, Chance MR, Miyagi M, Gudkov AV, Stark GR. Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65.  Nat. Acad. Sci. USA.2010; 107(1):46-51. PubMed [journal] PMID: 20080798, PMCID: PMC2806709

Lu T, Jackson MW, Singhi AD, Kandel ES, Yang M, Zhang Y, Gudkov AV, Stark GR. Validation-based insertional mutagenesis identifies lysine demethylase FBXL11 as a negative regulator of NF-κB.  Nat. Acad. Sci. USA.2009; 106(38):16339-44. PubMed [journal] PMID: 19805303, PMCID: PMC2736141

Faculty Research Team

Tao Lu, PhD

Tao Lu, PhD

Assistant Professor of Pharmacology & Toxicology
Dr. Lu’s background is in signaling transduction, molecular and cellular biology, biochemistry, genetics and pharmacology, with specific expertise in NF-kB signaling.

Additional Research Team Members

Lakshmi Prabhu, IBMG PhD student
Antja-Voy Hartley, IBMG PhD student
Matthew Martin, IBMG PhD student
Jiamin Jin, visiting PhD student
Mengyao Sun, MS. visiting scholar