Exploration of degraders of SNX9 that highly expresses in arteriovenous malformations

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K18413
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56070:Plastic and reconstructive surgery-related
• Research Institution: Ehime University
• Principal Investigator: SANADA SAYOKO 愛媛大学, 医学部附属病院, 助教 (60866044)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 血管新生 / ケラチノサイト / 動静脈奇形 / 皮膚悪性腫瘍

Outline of Final Research Achievements

SPOP is a scaffold protein for the ubiquitin ligase complex that binds to SNX9. We investigated the physiological roles of SPOP during DNA replication and DNA repair process in non-cancerous human keratinocytes-derived HaCaT cells. We found that SPOP knockdown remarkably reduced cell proliferation and arrested their cell cycles at G1/S phases in HaCaT cells. As mechanisms, the protein expression of DNA replication licensing factors CDT1 and CDC6 were suppressed remarkably as their translation was inhibited in SPOP-depleted HaCaT cells (Sanada, et al., BBRC. 2023). Our results suggest that SPOP is essential for DNA replication licensing in HaCaT cells.

Free Research Field

DNA合成

Academic Significance and Societal Importance of the Research Achievements

SPOPはHaCaT細胞においてDNA複製開始前段階からライセンス化因子であるCDT1とCDC6のタンパク質発現レベルを翻訳過程で適切に制御することで、DNA複製ストレスを緩和させる機能を発揮している可能性がある。日本版がんゲノムアトラスでは皮膚扁平上皮癌の約30%でSPOP遺伝子のコピー数の減少を認めており、SPOPの機能低下はDNA複製ストレスを増幅することで、発癌感受性の増大を来すことが本研究において示唆された。今後、SPOPが皮膚扁平上皮癌の診断マーカーや治療薬候補になると期待される。