Elevated NSD3 histone methylation activity drives squamous cell lung cancer.

Area of Science:

• Oncology
• Genetics
• Epigenetics

Background:

• Amplification of the 8p11-12 chromosomal region is common in lung squamous cell carcinoma (LUSC).
• FGFR1 has been considered a primary driver, but FGFR1 inhibition has failed in clinical trials.
• NSD3, a histone H3 lysine 36 methyltransferase located in the 8p11-12 amplicon, is investigated as a potential driver.

Purpose of the Study:

• To identify the key driver of tumorigenesis within the 8p11-12 amplicon in LUSC.
• To investigate the role of NSD3 in LUSC development and its therapeutic implications.
• To explore the therapeutic vulnerability of NSD3-dependent LUSC.

Main Methods:

• Correlation analysis of NSD3 expression and gene amplification in LUSC.
• In vitro and in vivo studies involving NSD3 ablation and variant expression in LUSC models.
• Structural dynamic analyses of NSD3 catalytic activity.
• Assessment of NSD3's role in human cell transformation and xenograft growth.
• Evaluation of bromodomain inhibition in NSD3-regulated LUSC xenografts.

Main Results:

• NSD3 expression strongly correlated with its gene amplification in LUSC, unlike FGFR1.
• Ablation of NSD3, but not FGFR1, reduced tumor growth and improved survival in a mouse model.
• An LUSC-associated variant, NSD3(T1232A), exhibited increased catalytic activity, accelerating tumorigenesis and decreasing survival.
• NSD3(T1232A) reprograms the chromatin landscape, promoting oncogenic gene expression.
• NSD3 depletion attenuated tumor growth in patient-derived xenografts, and NSD3-regulated xenografts were sensitive to bromodomain inhibition.

Conclusions:

• NSD3 is identified as a principal oncogenic driver in LUSC associated with the 8p11-12 amplicon.
• NSD3 catalytic activity and its variant NSD3(T1232A) are crucial for LUSC tumorigenesis.
• NSD3 dependency renders LUSC therapeutically vulnerable to bromodomain inhibition.