Research for unveiled molecular mechanism underlying cancer malignancy

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16350
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Tohoku University
• Principal Investigator: Okazaki Keito 東北大学, 加齢医学研究所, 助教 (70826289)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: NRF2 / NOTCH3 / CEBPB

Outline of Final Research Achievements

We found that persistently activated NRF2 in non-small cell lung cancer generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. These enhancers regulate NRF2-activated cancer specific target genes. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes not only tumor-initiating activity but also drug resistance and drives malignancy of NRF2-activated NSCLCs.

Free Research Field

肺がんの基礎研究

Academic Significance and Societal Importance of the Research Achievements

私達は、NRF2活性化がんに特徴的なNRF2の働きを明らかにすることで、がん幹細胞性に必須なゲノム領域を同定した。そして、その領域の働きにより産生されるNOTCH3タンパク質が、NRF2活性化がんという難治性がんに対する新しい治療標的として有効であることを見出した。NRF2活性化がんは、がんの遺伝子変異の解析から診断可能であることから、本研究成果は、がんの遺伝子診断に基づいたオーダーメイドがん治療のさきがけとなることが期待される。