Event Title

NSD Histone Methyltransferases drive Cell Proliferation in HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC)

Session Number

Project ID: MEDH 03

Advisor(s)

Dr. Yanis Boumber, Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Iuliia Topchu, Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Discipline

Medical and Health Sciences

Start Date

20-4-2022 10:05 AM

End Date

20-4-2022 10:20 AM

Abstract

Histone modifications are essential in regulating chromatin function and structure. Abnormal histone methylation is often detected during tumor development and progression. NSD1, NSD2, and NSD3 are key histone methyltransferases (HMTs) that catalyze lysine 36 dimethylation (K36me2) at histone H3. Inactivating NSD1 mutations are frequent in head neck squamous cell carcinoma (HNSCC) commonly occur in HPV-negative oropharyngeal (OP) carcinoma and laryngeal carcinomas (LC) and define a novel prognostic subtype in LC, where they associate with dramatically improved overall and progression-free survival. Here, we explored the biological impact of the loss of function of NSD1 in head neck squamous carcinoma (HNSCC). We discovered that HNSCC cells with a damaging mutation in NSD1 have reduced

K36me2 methylation levels relative to NSD1 wild-type HNSCC cells. We als found slower cell proliferation in NSD1 mutant cell line (SCC4) in comparison with other NSD1 WT cell lines. To further investigate the biologic impact of NSDs, we knocked down NSD1 and NSD2 with shRNA in different histologic subtypes of HNSCC cell lines (JHU011, JHU022, Cal27, and FaDu cell lines). The depletion of NSD1 and NSD2 results in a reduction of K36me2 and a significant decrease in cell proliferation and clonogenic formation in HNSCC, but not in lung cancer cells. Next, we performed a flow cytometry-based assay and found that NSD1/NSD2 depletion in HNSCC cells causes a significant increase in apoptosis levels. Downstream signaling, gene expression effects, and possible cell cycle regulation by NSD enzymes remain to be investigated in more detail. Ultimately, NSDs serve as attractive candidates for drug development, and targeting NSD1/NSD2 enzymes may be a new strategy for improving outcomes in HNSCC patients.

Share

COinS
 
Apr 20th, 10:05 AM Apr 20th, 10:20 AM

NSD Histone Methyltransferases drive Cell Proliferation in HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC)

Histone modifications are essential in regulating chromatin function and structure. Abnormal histone methylation is often detected during tumor development and progression. NSD1, NSD2, and NSD3 are key histone methyltransferases (HMTs) that catalyze lysine 36 dimethylation (K36me2) at histone H3. Inactivating NSD1 mutations are frequent in head neck squamous cell carcinoma (HNSCC) commonly occur in HPV-negative oropharyngeal (OP) carcinoma and laryngeal carcinomas (LC) and define a novel prognostic subtype in LC, where they associate with dramatically improved overall and progression-free survival. Here, we explored the biological impact of the loss of function of NSD1 in head neck squamous carcinoma (HNSCC). We discovered that HNSCC cells with a damaging mutation in NSD1 have reduced

K36me2 methylation levels relative to NSD1 wild-type HNSCC cells. We als found slower cell proliferation in NSD1 mutant cell line (SCC4) in comparison with other NSD1 WT cell lines. To further investigate the biologic impact of NSDs, we knocked down NSD1 and NSD2 with shRNA in different histologic subtypes of HNSCC cell lines (JHU011, JHU022, Cal27, and FaDu cell lines). The depletion of NSD1 and NSD2 results in a reduction of K36me2 and a significant decrease in cell proliferation and clonogenic formation in HNSCC, but not in lung cancer cells. Next, we performed a flow cytometry-based assay and found that NSD1/NSD2 depletion in HNSCC cells causes a significant increase in apoptosis levels. Downstream signaling, gene expression effects, and possible cell cycle regulation by NSD enzymes remain to be investigated in more detail. Ultimately, NSDs serve as attractive candidates for drug development, and targeting NSD1/NSD2 enzymes may be a new strategy for improving outcomes in HNSCC patients.