Inhibition of the MITF transcriptional activity by histone deacetylase 4 through SUMOylation

• Project/Area Number: 18K07031
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Aichi Medical University
• Principal Investigator: MURAKAMI HIDEKI 愛知医科大学, 医学部, 教授 (90303619)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: メラノーマ / MITF / SUMO化 / SUMO / HDAC4 / 悪性黒色腫

Outline of Final Research Achievements

The MITF is a lineage-specific oncogene in melanoma. The transcriptional activity of the MITF is regulated by post-translational modifications, including phosphorylation, ubiquitination and SUMOylation. In this study, we show that HDAC4 represses the transcriptional activity of the MITF through enhanced SUMOylation. Expression of HDAC4 was correlated with SUMOylation of MITF in melanoma specimens and cell lines. Activation of calcium/calmodulin-dependent protein kinase (CaMK) signaling promoted disrupting MITF-HDAC4 complexes and stimulating HDAC4 nuclear export. The upregulation of MITF sumoylation via the use of inhibitors of CaMK pathway could represent a valid anti-melanoma strategy.

Academic Significance and Societal Importance of the Research Achievements

悪性黒色腫は悪性度の高い皮膚腫瘍で、転移した場合は予後は極めて不良である。根治切除不能のメラノーマの対してはBRAFおよびMEK阻害剤などの有効性が確認されているが、薬剤耐性などにより持続的な効果が得られないことがある。BFAF阻害に対する耐性機構の一つとして転写因子MITF遺伝子の増幅などによる活性化が関与している。本研究ではHDAC4がMITFのSUMO化を促進することにより活性化に抑制的に働くことを明らかにした。HDAC4はCaMKによるリン酸化により局在が制御されており、CaMK阻害によるHDACを介したMITFの活性制御がBRAF阻害剤耐性に有効である可能性が示唆された。

Research Products

• [Journal Article] Identification of CD24 as a potential diagnostic and therapeutic target for malignant pleural mesothelioma (2020)
  • Author(s): KarnanS, Ota A, Murakami H, Rahman ML, Hasan MN, Wahiduzzaman MD, Hanamura I, Vu LQ, Inoko A, Hyodo T, Konishi H, Tsuzuki S, Hosokawa Y.
  • Journal Title: Cell Death Discovery Volume: 18 Issue: 1 Pages: 127-139
  • DOI: 10.1038/s41420-020-00364-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Establishment and characterization of CRISPR/Cas9-mediated NF2-/- human mesothelial cell line: Molecular insight into FGFR2 in MPM. (2019)
  • Author(s): Wahiduzzaman M, Karnan S, Ota A, Hanamura I, Murakami H, Inoko A, Rahman ML, Hyodo T, Konishi H, Tsuzuki S, Hosokawa Y.
  • Journal Title: Cancer Science Volume: 110 Pages: 180-193
  • Peer Reviewed