Functional mapping of epigenetic regulators uncovers coordinated tumor suppression by the HBO1 and MLL1 complexes

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Epigenetic alterations are common in cancer, but specific regulators driving cancer remain unclear.
• Understanding epigenetic drivers is crucial for developing targeted cancer therapies.

Purpose of the Study:

• To identify novel epigenetic regulators involved in KRAS-driven lung tumorigenesis using a high-throughput in vivo screen.
• To elucidate the functional roles of identified epigenetic regulators in lung cancer development and progression.

Main Methods:

• Utilized a novel, scalable, high-throughput in vivo functional screening method.
• Screened over 250 epigenetic regulatory genes in autochthonous oncogenic KRAS-driven lung tumors.
• Analyzed histone modifications, chromatin accessibility, and gene expression in identified complexes.

Main Results:

• Identified novel epigenetic tumor suppressor and tumor dependency genes.
• The HBO1 complex and MLL1 complex were found to be critical tumor suppressive epigenetic regulators in lung cancer.
• HBO1 complex-generated histone modifications are reduced in human lung adenocarcinomas.
• HBO1 and MLL1 complexes regulate chromatin accessibility, lineage fidelity, and tumor suppressor gene expression.
• These complexes are epistatic during lung tumorigenesis and functionally correlated in human cancer cell lines.

Conclusions:

• Quantitative in vivo screening provides a phenotypic roadmap of epigenetic regulators in tumorigenesis.
• HBO1 and MLL1 complexes represent promising therapeutic targets for lung adenocarcinoma.
• Epigenetic dysregulation by these complexes plays a significant role in lung cancer progression.