KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

Hinohara, Kunihiko; Wu, Hua‐Jun; Vigneau, Sébastien; McDonald, Thomas O.; Igarashi, Kyomi J.; Yamamoto, Kimiyo N.; Madsen, Thomas; Fassl, Anne; Egri, Shawn B.; Papanastasiou, Malvina; Ding, Lei; Peluffo, Guillermo; Cohen, Ofir; Kales, Stephen C.; Lal‐Nag, Madhu; Rai, Ganesha; Maloney, David J.; Jadhav, Ajit; Simeonov, Anton; Wagle, Nikhil; Brown, Myles; Meissner, Alexander; Siciński, Piotr; Jaffe, Jacob D.; Jeselsohn, Rinath; Gimelbrant, Alexander A.; Michor, Franziska; Polyák, Kornélia

doi:10.1016/j.ccell.2019.01.012

Cited by 35 publications

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“…Although ADT is effective in debulking tumors in most cases, the majority of treated PCa patients develop ADT resistance leading to emergence of more aggressive castration-resistant PCa (CRPC), which is the primary cause of PCa related deaths [2]. Development of acquired resistance to therapeutic regimens is common in virtually all targeted therapies and recent research implicates intratumor heterogeneity [3,4]. Intratumor heterogeneity is maintained partly through the expression of distinct sets of genes among tumor cells, a phenomenon called cellular transcriptomic heterogeneity (CTH) [4], which is controlled by transcription factors and histone-modifying enzymes [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…Development of acquired resistance to therapeutic regimens is common in virtually all targeted therapies and recent research implicates intratumor heterogeneity [3,4]. Intratumor heterogeneity is maintained partly through the expression of distinct sets of genes among tumor cells, a phenomenon called cellular transcriptomic heterogeneity (CTH) [4], which is controlled by transcription factors and histone-modifying enzymes [3][4][5][6]. These enzymes work through regulating chromatin structure, which is an important determinant of gene activity.…”

Section: Introductionmentioning

confidence: 99%

“…Genes involved in organogenesis and development are often dysregulated in tumorigenesis. Not surprisingly, KDM5B is overexpressed, and has been reported to play an oncogenic function, in a variety of cancers including breast cancer [4,22], melanoma [26], PCa [27], lung cancer [28], hepatocellular carcinoma [29], gastric cancer [30], neuroblastoma [31] and leukemia [32]. On the other hand, potential tumor-suppressive functions of KDM5B have also been documented in some cases of melanoma and subtypes of breast cancer [33,34].…”

Section: Introductionmentioning

confidence: 99%

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Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer

et al. 2020

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer

et al. 2020

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“…The role of gene expression variability in the appearance of therapeutic resistance independently of genetic variations is now demonstrated [110, 111]. Thus targeting this fundamental property of cancer cells, and especially of CSC, seems to be of major importance.…”

Section: A New Perspective On Cancer Stem Cellsmentioning

confidence: 99%

Cancer Stem Cells: From Historical Roots to a New Perspective

Capp

2019

Journal of Oncology

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The relationships between cancer and stemness have a long history that is traced here. From the mid-19th century when the first theory on the embryonic origin of cancer was formulated to works on embryonal carcinoma cells in the mid-20th century, many steps have been crossed leading to the current cancer stem cell theory postulating that tumor growth is supported by a small fraction of the tumoral cells that have stem-like properties. However, in the last fifteen years, many works regularly encourage us to revise the concept of cancer stem cell. This article mentions key results that lead to a new perspective where cancer stem cells are primarily seen as cells exhibiting increased epigenetic plasticity and increased gene expression variability. This perspective suggests new therapeutical interventions consisting in stabilizing gene expression to control cancer cell proliferation and prevent stochastic gene expression variations that could lead to therapeutic resistance.

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“…Such heterogeneity may result from secondary genetic mutations. In many cases, however, it cannot be linked to a clear genetic cause, but rather appears to be associated with epigenetic factors established by a cell's developmental lineage or differentiation state [2][3][4][5][6][7][8][9][10] . A paradigmatic example of epigenetic heterogeneity in the state of oncogene dependency is observed among melanomas that carry V600E/D/K mutations in the BRAF oncogene.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic modulation reveals differentiation state specificity of oncogene addiction

Khaliq

Manikkam

Martínez

et al. 2020

Preprint

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The hyperactivation of MAPK signaling pathway motivates the clinical use of MAPK inhibitors to treat BRAF-mutant melanomas. Heterogeneity in differentiation state due to epigenetic plasticity, however, results in cell-to-cell variability in the state of MAPK dependency and diminishes the efficacy of MAPK inhibitors. To identify key regulators of such variability and potential mitigation strategies, we screened 276 epigenetic-modifying compounds, individually and in combination with MAPK inhibitors, across both genetically distinct and isogenic populations of melanoma cells. Integrated with single-cell analysis and multivariate modeling, we identified three classes of epigenetic inhibitors that target seemingly distinct epigenetic states associated with either one of the lysine-specific histone demethylases KDM1A, or KDM4B, or BET bromodomain proteins. While melanocytes remained insensitive, the anti-tumor efficacy of each inhibitor was predicted based on a melanoma cell's differentiation state and MAPK activity. Our systems pharmacology approach highlights an avenue toward identifying actionable epigenetic factors that extend the BRAF oncogene addiction paradigm on the basis of tumor cell differentiation state.

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KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

Cited by 35 publications

References 0 publications

Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer

Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer

Cancer Stem Cells: From Historical Roots to a New Perspective

Epigenetic modulation reveals differentiation state specificity of oncogene addiction

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