Euchromatic histone methyltransferase 2 inhibitor, BIX-01294, sensitizes human promyelocytic leukemia HL-60 and NB4 cells to growth inhibition and differentiation

Savickienė, Jūratė; Treigytė, Gražina; Stirblytė, Ieva; Valiulienė, Giedrė; Navakauskienė, Rūta

doi:10.1016/j.leukres.2014.04.003

Cited by 28 publications

(19 citation statements)

References 30 publications

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“…Treatment with this inhibitor blocked epithelial-to-mesenchymal transition in cell culture and in in vivo models of breast cancer (Dong et al 2012), and reduced proliferation rates of some leukemia cell lines (Savickiene et al 2014). BIX-01294 causes significant cellular toxicity separate from its function inhibiting G9a and GLP, limiting its usefulness in preclinical research.…”

Section: Molecular Mechanisms Of Set Domain Nonhistone Methylation Inmentioning

confidence: 99%

Nonhistone Lysine Methylation in the Regulation of Cancer Pathways

Carlson

Gozani

2016

Cold Spring Harb Perspect Med

100

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Proteins are regulated by an incredible array of posttranslational modifications (PTMs). Methylation of lysine residues on histone proteins is a PTM with well-established roles in regulating chromatin and epigenetic processes. The recent discovery that hundreds and likely thousands of nonhistone proteins are also methylated at lysine has opened a tremendous new area of research. Major cellular pathways involved in cancer, such as growth signaling and the DNA damage response, are regulated by lysine methylation. Although the field has developed quickly in recent years many fundamental questions remain to be addressed. We review the history and molecular functions of lysine methylation. We then discuss the enzymes that catalyze methylation of lysine residues, the enzymes that remove lysine methylation, and the cancer pathways known tobe regulated by lysine methylation. The rest of the article focuses on two open questions that we suggest as a roadmap for future research. First is understanding the large number of candidate methyltransferase and demethylation enzymes whose enzymatic activity is not yet defined and which are potentially associated with cancer through genetic studies. Second is investigating the biological processes and cancer mechanisms potentially regulated by the multitude of lysine methylation sites that have been recently discovered.

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Section: Molecular Mechanisms Of Set Domain Nonhistone Methylation Inmentioning

confidence: 99%

Nonhistone Lysine Methylation in the Regulation of Cancer Pathways

Carlson

Gozani

2016

Cold Spring Harb Perspect Med

100

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“…BIX01294, a specific inhibitor of G9a29, induced autophagy or autophagy-associated cell death in several tumor cell lines3031323334, but underlying mechanisms have not been explored in glioma cells. Treatment with BIX01294 reduced methylation of H3K9 and H3K27, and at higher concentrations impaired viability of rat C6 glioma cells35.…”

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confidence: 99%

BIX01294, an inhibitor of histone methyltransferase, induces autophagy-dependent differentiation of glioma stem-like cells

Ciechomska

Przanowski

Jackl

et al. 2016

Sci Rep

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Glioblastoma (GBM) contains rare glioma stem-like cells (GSCs) with capacities of self-renewal, multi-lineage differentiation, and resistance to conventional therapy. Drug-induced differentiation of GSCs is recognized as a promising approach of anti-glioma therapy. Accumulating evidence suggests that unique properties of stem cells depend on autophagy. Here we demonstrate that BIX01294, an inhibitor of a G9a histone methyltransferase (introducing H3K9me2 and H3K27me3 repressive marks) triggers autophagy in human glioma cells. Pharmacological or genetic inhibition of autophagy decreased LC3-II accumulation and GFP-LC3 punctation in BIX01294-treated cells. GSCs-enriched spheres originating from glioma cells and GBM patient-derived cultures express lower levels of autophagy related (ATG) genes than the parental glioma cell cultures. Typical differentiation inducers that upregulate neuronal and astrocytic markers in sphere cultures, increase the level of ATG mRNAs. G9a binds to the promoters of autophagy (LC3B, WIPI1) and differentiation-related (GFAP, TUBB3) genes in GSCs. Higher H3K4me3 (an activation mark) and lower H3K9me2 (the repressive mark) levels at the promoters of studied genes were detected in serum-differentiated cells than in sphere cultures. BIX01294 treatment upregulates the expression of autophagy and differentiation-related genes in GSCs. Pharmacological inhibition of autophagy decreases GFAP and TUBB3 expression in BIX01294-treated GSCs suggesting that BIX01294-induced differentiation of GSCs is autophagy-dependent.

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“…Epigenetic-based drugs targeting epigenetic enzymes in cancer have been shown to affect GSC differentiation and induce autophagy [69,71]. BIX01294, a specific inhibitor of G9a histone methyltransferase (introducing H3K9me2 and H3K27me3 repressive marks) [72], induced autophagy or autophagy-associated cell death in many tumor cell lines [73][74][75][76][77], but underlying mechanisms have not been explored in glioma cells. Additionally, BIX01294 is a potent modulator of stem cell differentiation.…”

Section: The Role Of Autophagy In Differentiation Of Glioma Stem-likementioning

confidence: 99%

Rola autofagii w komórkach nowotworowych: charakterystyka wzajemnych zależności pomiędzy procesami autofagii i apoptozy; modulacja autofagii jako nowa strategia terapeutyczna w leczeniu glejaków

Ciechomska¹

2018

Postepy Biochem

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W 2016 roku nagrodę Nobla w dziedzinie medycyny i fizjologii otrzymał japoński naukowiec Yoshinori Ohsumi, za odkrycie molekularnych mechanizmów leżących u podstaw autofagii. Odkrycie to miało fundamentalne znaczenie w zrozumieniu w jaki sposób komórka poddaje recyklingowi swoją zawartość. Jego odkrycie utorowało drogę do zrozumienia wielu procesów fizjologicznych takich jak adaptacja do warunków niedoboru substancji odżywczych czy odpowiedz na infekcję patogenami. Ponadto mutacje genów regulujących proces autofagii mogą przyczyniać się do rozwoju wielu chorób, w tym nowotworów czy chorób neurodegeneracyjnych. Pokazuje to, jak ważne są badania dotyczące autofagii i jak istotną rolę odgrywa ten proces zarówno w stanach fizjologicznych i patologicznych. Wciąż wiele pytań pozostaje jednak bez odpowiedzi m.in. zagadnienie funkcji autofagii w komórkach nowotworowych. Celem omawianych prac było przybliżenie roli autofagii w komórkach nowotworowych poprzez ocenę niektórych metod detekcji autofagii, określenie molekularnych współzależności pomiędzy autofagią i apoptozą w komórkach nowotworowych, a także poszukiwanie nowych strategii leczenia najczęstszych nowotworów mózgu, glejaków.

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Euchromatic histone methyltransferase 2 inhibitor, BIX-01294, sensitizes human promyelocytic leukemia HL-60 and NB4 cells to growth inhibition and differentiation

Cited by 28 publications

References 30 publications

Nonhistone Lysine Methylation in the Regulation of Cancer Pathways

Nonhistone Lysine Methylation in the Regulation of Cancer Pathways

BIX01294, an inhibitor of histone methyltransferase, induces autophagy-dependent differentiation of glioma stem-like cells

Rola autofagii w komórkach nowotworowych: charakterystyka wzajemnych zależności pomiędzy procesami autofagii i apoptozy; modulacja autofagii jako nowa strategia terapeutyczna w leczeniu glejaków

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