Hai Yan

Overview:

Our research activities center on the molecular genetics and biology of cancer with a focus on the identification, characterization, and therapeutic targeting of driver mutations involved in the genesis and progression of brain cancers.  Gliomas are the most common type of primary brain tumor. Through genomic studies, we have identified mutations in IDH1 and IDH2 in 70% of progressive malignant gliomas. These are somatic missense mutations that alter a conserved arginine residue and gain a neomorphic activity. A new metabolite produced by the glioma cells impacts on chromatin modulation and genome methylation.  Malignant cells must maintain their telomeres. We identified several different tumor types exhibiting a high frequency of TERT promoter mutations, including several glioma subtypes. Conversely, we found a low frequency of TERT promoter mutations in many common epithelial tumors.  In gliomas, we found that TERT promoter mutations were mutually exclusive with ATRX alterations, which are associated with activation of the ALT pathway for telomere maintenance. These findings show that TERT promoter mutations are frequent driver events in many human cancers, particularly those that arise from tissues with low rates of self-renewal. Our long-term goal is to develop a novel molecular-based glioma classification system and a targeted therapy on the basis of IDH1 and TERT mutations. To provide novel avenues for development of anticancer therapeutics, studies involving cell line and animal models, enzymatic study, metabolome and epigenome, are being investigated to determine the consequences of IDH1 and TERT mutations on cancer cells.

Positions:

Henry S. Friedman Distinguished Professor of Neuro-Oncology in the School of Medicine

Pathology
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1991

Beijing Medical University (China)

Ph.D. 1997

Columbia University

Research Associate, Howard Hughes Institute

Johns Hopkins University

Faculty, Research Associate, Molecular Genetics

Thomas Jefferson University

Publications:

Genome-wide CRISPR-Cas9 screen reveals selective vulnerability of ATRX-mutant cancers to WEE1 inhibition.

The tumor suppressor gene ATRX is frequently mutated in a variety of tumors including gliomas and liver cancers, which are highly unresponsive to current therapies. Here, we performed a genome-wide synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for ATRX-mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase WEE1, uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines in vitro, as well as xenografts in vivo. The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring ATRX mutations, indicating that the synthetic lethal relationship between WEE1 and ATRX could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in ATRX.
Authors
Liang, J; Zhao, H; Diplas, BH; Liu, S; Liu, J; Wang, D; Lu, Y; Zhu, Q; Wu, J; Wang, W; Yan, H; Zeng, Y-X; Wang, X; Jiao, Y
MLA Citation
Liang, Junbo, et al. “Genome-wide CRISPR-Cas9 screen reveals selective vulnerability of ATRX-mutant cancers to WEE1 inhibition..” Cancer Res, Sept. 2019. Pubmed, doi:10.1158/0008-5472.CAN-18-3374.
URI
https://scholars.duke.edu/individual/pub1411833
PMID
31551363
Source
pubmed
Published In
Cancer Res
Published Date
DOI
10.1158/0008-5472.CAN-18-3374

A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis.

H2AX safeguards genomic stability in a dose-dependent manner; however, mechanisms governing its proteostasis are poorly understood. Here, we identify a PRMT5-RNF168-SMURF2 cascade that regulates H2AX proteostasis. We show that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for DNA damage response (DDR). Suppression of PRMT5 occurs in methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells and attenuates the expression of RNF168, leading to destabilization of H2AX by E3 ubiquitin ligase SMURF2. RNF168 and SMURF2 serve as a stabilizer and destabilizer of H2AX, respectively, via their dynamic interactions with H2AX. In supporting an important role of this signaling cascade in regulating H2AX, MTAP-deficient glioblastoma cells display higher levels of DNA damage spontaneously or in response to genotoxic agents. These findings reveal a regulatory mechanism of H2AX proteostasis and define a signaling cascade that is essential to DDR and that is disrupted by the loss of a metabolic enzyme in tumor cells.
Authors
Du, C; Hansen, LJ; Singh, SX; Wang, F; Sun, R; Moure, CJ; Roso, K; Greer, PK; Yan, H; He, Y
MLA Citation
Du, Changzheng, et al. “A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis..” Cell Rep, vol. 28, no. 12, Sept. 2019, pp. 3199-3211.e5. Pubmed, doi:10.1016/j.celrep.2019.08.031.
URI
https://scholars.duke.edu/individual/pub1410992
PMID
31533041
Source
pubmed
Published In
Cell Reports
Volume
28
Published Date
Start Page
3199
End Page
3211.e5
DOI
10.1016/j.celrep.2019.08.031

The potential of cerebrospinal fluid-based liquid biopsy approaches in CNS tumors.

Cerebrospinal fluid (CSF) may be the best hope for minimally invasive diagnosis and treatment monitoring of central nervous system (CNS) malignancies. Discovery/validation of cell-free nucleic acid and protein biomarkers has the potential to revolutionize CNS cancer care, paving the way for presurgical evaluation, earlier detection of recurrence, and the selection of targeted therapies. While detection of mutations, changes in RNA and miRNA expression, epigenetic alterations, and elevations of protein levels have been detected in the CSF of patients with CNS tumors, most of these biomarkers remain unvalidated. In this review, we focus on the molecular changes that have been identified in a variety of CNS tumors and profile the approaches used to detect these alterations in clinical samples. We further emphasize the importance of systemic collection of CSF and the establishment of standardized collection protocols that will lead to better cross-study biomarker validation and hopefully FDA-approved clinical markers.
Authors
Mattox, AK; Yan, H; Bettegowda, C
MLA Citation
Mattox, Austin K., et al. “The potential of cerebrospinal fluid-based liquid biopsy approaches in CNS tumors..” Neuro Oncol, vol. 21, no. 12, Dec. 2019, pp. 1509–18. Pubmed, doi:10.1093/neuonc/noz156.
URI
https://scholars.duke.edu/individual/pub1415354
PMID
31595305
Source
pubmed
Published In
Neuro Oncol
Volume
21
Published Date
Start Page
1509
End Page
1518
DOI
10.1093/neuonc/noz156

CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP.

Mutations in isocitrate dehydrogenases 1 and 2 (IDH) occur in the majority of World Health Organization grade II and III gliomas. IDH1/2 active site mutations confer a neomorphic enzyme activity producing the oncometabolite D-2-hydroxyglutarate (D-2HG), which generates the glioma CpG island methylation phenotype (G-CIMP). While IDH1/2 mutations and G-CIMP are commonly retained during tumor recurrence, recent work has uncovered losses of the IDH1 mutation in a subset of secondary glioblastomas. Cooccurrence of the loss of the mutant allele with extensive methylation changes suggests a possible link between the two phenomena. Here, we utilize patient-derived IDH1R132H/WT glioma cell lines and CRISPR-Cas9-mediated gene knockout to model the genetic loss of IDH1R132H, and characterize the effects of this deletion on DNA methylation. After D-2HG production has been abolished by deletions within the IDH1 alleles, these models show persistent DNA hypermethylation at seven CpG sites previously used to define G-CIMP-positivity in patient tumor samples. Despite these defining G-CIMP sites showing persistent hypermethylation, we observed a genome-wide pattern of DNA demethylation, enriched for CpG sites located within open sea regions of the genome, as well as in CpG-island shores of transcription start sites, after loss of D-2HG production. These results suggest that inhibition of D-2HG from genetic deletion of IDH alleles is not sufficient to reverse hypermethylation of all G-CIMP-defining CpG sites, but does result in more demethylation globally and may contribute to the formation of a G-CIMP-low-like phenotype. IMPLICATIONS: These findings show that loss of the IDH1 mutation in malignant glioma cells leads to a pattern of DNA methylation alterations, and shows plausibility of IDH1 mutation loss being causally related to the gain of a G-CIMP-low-like phenotype.
Authors
Moure, CJ; Diplas, BH; Chen, LH; Yang, R; Pirozzi, CJ; Wang, Z; Spasojevic, I; Waitkus, MS; He, Y; Yan, H
MLA Citation
Moure, Casey J., et al. “CRISPR Editing of Mutant IDH1 R132H Induces a CpG Methylation-Low State in Patient-Derived Glioma Models of G-CIMP..” Mol Cancer Res, vol. 17, no. 10, Oct. 2019, pp. 2042–50. Pubmed, doi:10.1158/1541-7786.MCR-19-0309.
URI
https://scholars.duke.edu/individual/pub1397070
PMID
31292202
Source
pubmed
Published In
Mol Cancer Res
Volume
17
Published Date
Start Page
2042
End Page
2050
DOI
10.1158/1541-7786.MCR-19-0309

Biological Role and Therapeutic Potential of IDH Mutations in Cancer.

Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in a variety of myeloid malignancies and solid tumors. Mutant IDH proteins acquire a neomorphic enzyme activity to produce the putative oncometabolite D-2-hydroxyglutarate, which is thought to block cellular differentiation by competitively inhibiting α-ketoglutarate-dependent dioxygenases involved in histone and DNA demethylation. Small-molecule inhibitors of mutant IDH1 and IDH2 have been developed and are progressing through pre-clinical and clinical development. In this review, we provide an overview of mutant IDH-targeted therapy and discuss a number of important recent pre-clinical studies using models of IDH-mutant solid tumors.
Authors
Waitkus, MS; Diplas, BH; Yan, H
MLA Citation
Waitkus, Matthew S., et al. “Biological Role and Therapeutic Potential of IDH Mutations in Cancer..” Cancer Cell, vol. 34, no. 2, Aug. 2018, pp. 186–95. Pubmed, doi:10.1016/j.ccell.2018.04.011.
URI
https://scholars.duke.edu/individual/pub1319608
PMID
29805076
Source
pubmed
Published In
Cancer Cell
Volume
34
Published Date
Start Page
186
End Page
195
DOI
10.1016/j.ccell.2018.04.011

Research Areas:

Adaptor Proteins, Signal Transducing
Adenocarcinoma
Adenocarcinoma, Clear Cell
Adenoma
Adenosine Triphosphatases
Adenosine Triphosphate
Adipates
Aged
Aged, 80 and over
Alcohol Oxidoreductases
Alleles
Alternative Splicing
Amino Acid Sequence
Animals
Annexin A5
Anoxia
Antibodies
Antibodies, Monoclonal
Antigens, CD4
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Arginine
Astrocytes
Astrocytoma
Base Pair Mismatch
Benzeneacetamides
Binding Sites
Blotting, Western
Brain Neoplasms
Burkitt Lymphoma
CD4 Antigens
Calpain
Carcinoma, Neuroendocrine
Carcinoma, Non-Small-Cell Lung
Carcinoma, Small Cell
Carcinoma, Squamous Cell
Carmustine
Catalytic Domain
Cell Differentiation
Cell Division
Cell Growth Processes
Cell Line
Cell Line, Transformed
Cell Line, Tumor
Cell Nucleus
Cell Proliferation
Cell Transformation, Neoplastic
Cells, Cultured
Central Nervous System Neoplasms
Cerebellar Neoplasms
Cerebellum
Chromatin
Chromatin Assembly and Disassembly
Chromatin Immunoprecipitation
Chromosome Aberrations
Chromosome Painting
Chromosomes
Chromosomes, Human, Pair 1
Chromosomes, Human, Pair 19
Chromosomes, Human, Pair 2
Chromosomes, Human, Pair 9
Cloning, Molecular
Codon
Codon, Nonsense
Cohort Studies
Colon
Colorectal Neoplasms
Computational Biology
CpG Islands
Cyclin-Dependent Kinase Inhibitor p18
Cytoplasm
DNA
DNA Copy Number Variations
DNA Helicases
DNA Methylation
DNA Mutational Analysis
DNA Primers
DNA Probes
DNA Repair
DNA, Complementary
DNA, Neoplasm
Dioxygenases
Dipeptides
Disease Progression
Dogs
Down-Regulation
Drug Resistance, Neoplasm
Endoplasmic Reticulum
Energy Metabolism
Enzyme Induction
Enzyme Inhibitors
Epigenesis, Genetic
Epigenomics
Escherichia coli
Exons
Female
Fibrosarcoma
Flow Cytometry
Fluorescent Dyes
Frameshift Mutation
Gene Amplification
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Gene Silencing
Genes, APC
Genes, Neoplasm
Genes, Reporter
Genes, Tumor Suppressor
Genes, erbB-1
Genes, myc
Genetic Complementation Test
Genetic Loci
Genetic Techniques
Genetic Variation
Genetics, Medical
Genome, Human
Genome-Wide Association Study
Genomics
Genotype
Germ-Line Mutation
Glioblastoma
Glioma
Glucose
Glutarates
Glutathione Transferase
Guanylate Cyclase
HCT116 Cells
Hematopoiesis
Histidine
Histone-Lysine N-Methyltransferase
Histones
Homeodomain Proteins
Humans
Hybridomas
Hypoxia
Hypoxia-Inducible Factor 1
Imidazoles
Immunoblotting
Immunohistochemistry
Immunoprecipitation
In Situ Hybridization, Fluorescence
Interferon Type I
Interferon-alpha
Interferon-gamma
Isocitrate Dehydrogenase
Isocitrates
Janus Kinase 1
Kaplan-Meier Estimate
Karyotyping
Ketoglutaric Acids
Kruppel-Like Transcription Factors
Lactates
Leukemia, Myeloid, Acute
Ligands
Loss of Heterozygosity
Lymphocytes
Magnetics
Male
Medulloblastoma
Melanoma
Metabolome
Methylation
Methylene Blue
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, Transgenic
MicroRNAs
Microsatellite Instability
Microsatellite Repeats
Microtubule-Associated Proteins
Middle Aged
Models, Biological
Models, Molecular
Molecular Sequence Data
Moths
MutS Homolog 2 Protein
Mutagenesis, Site-Directed
Mutant Proteins
Mutation
Mutation, Missense
Neoplasm Grading
Neoplasm Transplantation
Neoplasms
Neoplasms, Experimental
Neural Stem Cells
Oligodendroglioma
Oncogenes
Otx Transcription Factors
Phenotype
Phenylurea Compounds
Phosphatidylinositol 3-Kinases
Phosphoric Monoester Hydrolases
Phosphotyrosine
Physical Chromosome Mapping
Point Mutation
Polymerase Chain Reaction
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Procollagen-Proline Dioxygenase
Prognosis
Promoter Regions, Genetic
Protein Biosynthesis
Protein Conformation
Protein Engineering
Protein Kinases
Protein Processing, Post-Translational
Protein Structure, Tertiary
Protein Tyrosine Phosphatase, Non-Receptor Type 13
Protein Tyrosine Phosphatase, Non-Receptor Type 3
Protein Tyrosine Phosphatases
Protein-Tyrosine Kinases
Proto-Oncogene Proteins
RNA Interference
RNA, Messenger
RNA, Small Interfering
Real-Time Polymerase Chain Reaction
Receptor Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Receptor, Interferon alpha-beta
Receptor, Notch2
Receptor, trkC
Receptor-Like Protein Tyrosine Phosphatases, Class 2
Receptor-Like Protein Tyrosine Phosphatases, Class 5
Receptors, Cell Surface
Receptors, Cytokine
Receptors, Interferon
Recombinant Fusion Proteins
Repressor Proteins
Reverse Transcriptase Polymerase Chain Reaction
Rhombencephalon
Risk Factors
S100 Proteins
STAT1 Transcription Factor
STAT2 Transcription Factor
Saccharomyces cerevisiae
Sequence Analysis, DNA
Sequence Deletion
Signal Transduction
Spodoptera
Stomach
Stomach Neoplasms
Streptolysins
Sulfonamides
Suppressor of Cytokine Signaling Proteins
Survival Rate
TYK2 Kinase
Telomerase
Telomere
Templates, Genetic
Tolonium Chloride
Trans-Activators
Transcription, Genetic
Transfection
Tretinoin
Tumor Cells, Cultured
Tumor Markers, Biological
Tumor Stem Cell Assay
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Tunicamycin
Tyrosine
Up-Regulation
Xenograft Model Antitumor Assays
Young Adult
src Homology Domains