Spatial and temporal regulation mechanism and its role of TGFbeta-induced Myc overexpression in osteosarcoma development and progression

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K21066
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0907:Oral science and related fields
• Research Institution: Nagasaki University
• Principal Investigator: Ueno Tomoya 長崎大学, 医歯薬学総合研究科(歯学系), 助教 (40968583)
• Project Period (FY): 2022-08-31 – 2024-03-31
• Keywords: 骨肉腫 / Runx / c-Myc / TGFβ

Outline of Final Research Achievements

We recently demonstrated that p53 inactivation and Myc overexpression, which are essential for OS development, are mediated by Runx transcription factors. However, the mechanisms inducing Myc upregulation by Runx in a p53-deficient microenvironment remain unclear.
We found that p53 disruption causes TGFβ to aberrantly induce Myc in osteoprogenitors. We identified its cognate enhancer (super enhancer) downstream of the Myc gene, which interacted with the Myc promoter upon TGFβ stimulation via chromatin looping.At this region, TGFβ promoted the occupancy of each member of a transcriptional complex consisting of Runx, its cooperative factors, AP1 and Smads, and CBP, further activating the enhancer by H3K27ac deposition.
These results suggest that Myc dysregulation are mediated by the epigenetic node, where TGFβ plays a pivotal role in collaboration with Runx to unleash Myc.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

がん抑制遺伝子p53とがん遺伝子Mycは、ヒトの悪性腫瘍に広く関わる代表的な遺伝子であり、これらを取り巻く分子機序の解明に多くの研究者が取り組んでいる。そのため、p53とMycがRunxやTGFβによって仲介されることを示した本研究成果は、骨肉腫以外の悪性腫瘍の研究にも繋がるだろう。特に、Myc過剰発現誘導の中核を成すTGFβ作動性転写装置は、骨肉腫だけでなく、他の悪性腫瘍の治療標的となる可能性を秘めている。