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Updated: Feb 14, 2026

Application of MassSQUIRM for Quantitative Measurements of Lysine Demethylase Activity
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Application of MassSQUIRM for Quantitative Measurements of Lysine Demethylase Activity

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Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma

Yong Yu1, Kolja Schleich2, Bin Yue2

  • 1Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.

Cancer Cell
|February 14, 2018
PubMed

Insights

Histone demethylases like LSD1 and JMJD2C disable cancer cell senescence, promoting melanoma. Inhibiting these enzymes restores senescence, even in resistant melanomas, and controls tumor growth.

Area of Science:

  • Molecular Biology
  • Oncology
  • Epigenetics

Background:

  • Oncogene-induced senescence halts pre-malignant cell proliferation via histone modifications.
  • Repressive trimethylated histone H3 lysine 9 (H3K9) marks silence proliferation genes in senescence.

Purpose of the Study:

  • To investigate the role of H3K9 demethylases in disabling senescence and promoting melanoma.
  • To evaluate the therapeutic potential of targeting H3K9 demethylases in melanoma.

Main Methods:

  • Utilized mouse and zebrafish models with enforced expression of LSD1 or JMJD2C.
  • Analyzed melanoma cell lines and human melanoma samples for H3K9 demethylase activity.
  • Assessed the effects of targeted H3K9 demethylase inhibition on senescence, immune response, and tumor growth in vivo.

Main Results:

  • Enforced expression of LSD1 or JMJD2C promoted Braf-V600E-driven melanomagenesis.
  • Upregulated H3K9 demethylase activities were observed in a significant portion of melanoma samples.
  • Targeted inhibition of H3K9 demethylases restored senescence, including in Braf inhibitor-resistant melanomas.
  • Inhibition also evoked secondary immune effects and controlled tumor growth.

Conclusions:

  • H3K9 demethylases (LSD1, JMJD2C) are key drivers in disabling oncogene-induced senescence, facilitating melanoma development.
  • Targeting these demethylases represents a promising therapeutic strategy for melanoma, overcoming resistance and engaging the immune system.
Keywords:
H3K9JMJD2CLSD1Ras/Brafanimal modelscellular senescencehistone demethylationmelanomapatient-derived xenografttargeted therapy

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