Epigenetic regulation of ANGPTL2 expression in cancer and lifestyle disease

• Project/Area Number: 25870543
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry; Tumor diagnostics
• Research Institution: Kumamoto University
• Principal Investigator: KADOMATSU Tsuyoshi 熊本大学, 大学院生命科学研究部, 助教 (90555757)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 癌 / 生活習慣病 / エピゲノム / 発現制御 / ANGPTL2 / 転移

Outline of Final Research Achievements

We showed that the tumor microenvironment, such as hypoxia and nutrient starvation, increased ANGPTL2 expression levels in osteosarcoma cells and decreased DNA methylation levels of its promoter. In addition, the tumor microenvironment induced expression of DNA demethylation-related enzymes in osteosarcoma cells. These results suggest that the tumor microenvironment induces ANGPTL2 expression in tumor cells by inducing DNA demethylation of its promoter. We also showed that tumor cell-derived ANGPTL2 enhanced tumor metastasis through promoting invasive activity of tumor cells and tumor cell intravasation. Furthermore, We found that full-length ANGPTL2 protein was extracellularly cleaved by TLL1 into an inactive form lacking the capacity to enhance tumor aggressiveness. Thus, strategies to promote cleavage of full-length ANGPTL2 by TLL1 could block metastasis.

Research Products

• [Journal Article] ANGPTL2 increases bone metastasis of breast cancer cells through enhancing CXCR4 signaling. (2015)
  • Author(s): Masuda T, Endo M, Yamamoto Y, Odagiri H, Kadomatsu T, Nakamura T, Tanoue H, Ito H, Yugami M, Miyata K, Morinaga J, Horiguchi H, Motokawa I, Terada K, Morioka MS, Manabe I, Iwase H, Mizuta H, Oike Y.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 9170-9170
  • DOI: 10.1038/srep09170
  • Peer Reviewed / Open Access
• [Journal Article] Angiopoietin-like protein 2 renders colorectal cancer cells resistant to chemotherapy by activating spleen tyrosine kinase-phosphoinositide 3-kinase-dependent anti-apoptotic signaling. (2014)
  • Author(s): Horiguchi H, Endo M, Miyamoto Y, Sakamoto Y, Odagiri H, Masuda T, Kadomatsu T, Tanoue H, Motokawa I, Terada K, Morioka MS, Manabe I, Baba H, Oike Y.
  • Journal Title: Cancer Science Volume: 105 Issue: 12 Pages: 1550-1559
  • DOI: 10.1111/cas.12554
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SIRT7 controls hepatic lipid metabolism by regulating the ubiquitin-proteasome pathway. (2014)
  • Author(s): Yoshizawa T, Karim Md. F, Sato Y, Senokuchi T, Miyata K, Fukuda T, Go C, Tasaki M, Uchimura K, Kadomatsu T, Tian Z, Smolka C, Sawa T, Kakeya M, Tomizawa K, Ando Y, Araki E, Akaike T, Braun T, Oike Y, Bober E, Yamagata K.
  • Journal Title: Cell Metab. Volume: 9 Issue: 4 Pages: 712-721
  • DOI: 10.1016/j.cmet.2014.03.006
  • Peer Reviewed / Open Access
• [Journal Article] Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression. (2014)
  • Author(s): Horio E, Kadomatsu T, Miyata K, Arai Y, Hosokawa K, Doi Y, et al.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 34 Issue: 4 Pages: 790-800
  • DOI: 10.1161/atvbaha.113.303116
  • Peer Reviewed / Open Access
• [Journal Article] Diverse roles of ANGPTL2 in physiology and pathophysiology. (2014)
  • Author(s): Kadomatsu T, Endo M, Miyata K, Oike Y.
  • Journal Title: Trends Endocrinol Metab. Volume: 25(5) Issue: 5 Pages: 245-54
  • DOI: 10.1016/j.tem.2014.03.012
  • Peer Reviewed / Open Access
• [Journal Article] The secreted protein ANGPTL2 promotes metastasis of osteosarcoma cells through integrin alpha5beta1, p38 MAPK, and matrix metalloproteinases. (2014)
  • Author(s): Odagiri et al.
  • Journal Title: Science Signaling Volume: 7 Issue: 309
  • DOI: 10.1126/scisignal.2004612
  • Peer Reviewed / Open Access
• [Presentation] 生活習慣病・がんの共通分子機構とアンジオポエチン様因子2シグナル (2014)
  • Author(s): 門松 毅、小田切 陽樹、遠藤 元誉、尾池 雄一
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-10-18
• [Presentation] The Tumor Microenvironment Accelerates Tumor Cell Invasivity and Metastasis through Epigenetic Regulation of ANGPTL2
  • Author(s): 門松 毅、小田切 陽樹、遠藤 元誉、舛田 哲朗、森岡 勝樹、宮田 敬士、青井 淳、堀口 晴紀、西村 尚剛、寺田 和豊、薬師寺 俊剛、真鍋 一郎、水田 博志、尾池 雄一
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド
• [Presentation] がん微小環境はエピジェネティックなANGPTL2の発現誘導を介してがんの浸潤・転移を促進する
  • Author(s): 門松 毅、小田切 陽樹、遠藤 元誉、舛田 哲朗、森岡 勝樹、福原 茂朋、宮本 健史、小林 英介、宮田 敬士、青井 淳、堀口 晴紀、西村 尚剛、寺田 和豊、薬師寺 俊剛、真鍋 一郎、望月 直樹、水田 博志、尾池 雄一
  • Organizer: 第10回宮崎サイエンスキャンプ
  • Place of Presentation: シーガイアコンベンションセンター
• [Remarks] 熊本大学大学院生命科学研究部 分子遺伝学分野
  • URL: http://molgene.kumamoto-u.ac.jp
• [Remarks] 熊本大学大学院生命科学研究部 分子遺伝学分野
  • URL: http://molegene.kumamoto-u.ac.jp