Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma

Auzmendi-Iriarte, Jaione; Saenz-Antoñanzas, Ander; Mikelez-Alonso, Idoia; Carrasco‐García, Estefanía; Tellaetxe-Abete, Maitena; Lawrie, Charles H.; Samprón, Nicolás; Cortajarena, Aitziber L.; Matheu, Ander

doi:10.1038/s41419-020-2586-x

Cited by 42 publications

(33 citation statements)

References 37 publications

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“…In combination with other anticancer drugs, HDAC6 inhibitor A542 suppresses the proliferation of follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), germinal center diffuse large Bcell lymphoma cells (DLBCL) and CRC by targeting HDAC6 (86,87). Furthermore, HDAC6 inhibitors such as JOC1, SKLB-23bb, MPT0G413 as well as MPT0G612 show great anticancer activity, whereas the cytoplasm toxic as well as the mechanism are to be further investigated (68,(88)(89)(90)(91).…”

Section: Small Molecules Targeting Hats Hdacs and Brds In Cancer Thmentioning

confidence: 99%

Small Molecules Targeting HATs, HDACs, and BRDs in Cancer Therapy

Qiu²,

Jiao

et al. 2020

Front. Oncol.

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Evidence for research over the past decade shows that epigenetic regulation mechanisms run through the development and prognosis of tumors. Therefore, small molecular compounds targeting epigenetic regulation have become a research hotspot in the development of cancer therapeutic drugs. According to the obvious abnormality of histone acetylation when tumors occur, it suggests that histone acetylation modification plays an important role in the process of tumorigenesis. Currently, as a new potential anti-cancer therapeutic drugs, many active small molecules that target histone acetylation regulatory enzymes or proteins such as histone deacetylases (HDACs), histone acetyltransferase (HATs) and bromodomains (BRDs) have been developed to restore abnormal histone acetylation levels to normal. In this review, we will focus on summarizing the changes of histone acetylation levels during tumorigenesis, as well as the possible pharmacological mechanisms of small molecules that target histone acetylation in cancer treatment.

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Section: Small Molecules Targeting Hats Hdacs and Brds In Cancer Thmentioning

confidence: 99%

Small Molecules Targeting HATs, HDACs, and BRDs in Cancer Therapy

Qiu²,

Jiao

et al. 2020

Front. Oncol.

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“…HDAC6 inhibitors can significantly reduce glioma cell proliferation by disrupting the G2/M transition, increasing cell death, and promoting cell cycle exit and tumor cell differentiation [ 1 , 7 , 8 ]. We first confirmed that our patient-derived L0 (high grade), S3 (high grade), and S7 (low grade) glioma cell lines are sensitive to HDAC6 inhibitors by treating dissociated cells in serum-free media with different concentrations of 1215 and 738.…”

Section: Resultsmentioning

confidence: 99%

“…Glioblastoma (GBM), the most common and lethal aggressive brain tumor in adults, usually becomes refractory to standard-of-care treatments that include surgery, irradiation, and temozolomide (TMZ) chemotherapy. Histone deacetylase 6 (HDAC6) is a therapeutic target in non-central nervous system (CNS) cancers that is receiving increasing scrutiny in GBM [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Compared to other HDACs, HDAC6 expression is disproportionately high in GBM [ 1 , 3 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Histone deacetylase 6 (HDAC6) is a therapeutic target in non-central nervous system (CNS) cancers that is receiving increasing scrutiny in GBM [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Compared to other HDACs, HDAC6 expression is disproportionately high in GBM [ 1 , 3 , 10 ]. Notably, HDAC6-specific inhibitors reduce the proliferation and viability of GBM cells in vitro [ 6 , 9 , 10 , 11 ] and in subcutaneous and orthotopic models of GBM [ 1 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Compared to other HDACs, HDAC6 expression is disproportionately high in GBM [ 1 , 3 , 10 ]. Notably, HDAC6-specific inhibitors reduce the proliferation and viability of GBM cells in vitro [ 6 , 9 , 10 , 11 ] and in subcutaneous and orthotopic models of GBM [ 1 , 12 ]. Lentiviral-mediated knockdown of HDAC6 also slows tumor growth and promotes survival in an intracranial model of GBM [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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HDAC6 Signaling at Primary Cilia Promotes Proliferation and Restricts Differentiation of Glioma Cells

Shi

Hoang-Minh

Tian

et al. 2021

Cancers

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Histone deacetylase 6 (HDAC6) is an emerging therapeutic target that is overexpressed in glioblastoma when compared to other HDACs. HDAC6 catalyzes the deacetylation of alpha-tubulin and mediates the disassembly of primary cilia, a process required for cell cycle progression. HDAC6 inhibition disrupts glioma proliferation, but whether this effect is dependent on tumor cell primary cilia is unknown. We found that HDAC6 inhibitors ACY-1215 (1215) and ACY-738 (738) inhibited the proliferation of multiple patient-derived and mouse glioma cells. While both inhibitors triggered rapid increases in acetylated alpha-tubulin (aaTub) in the cytosol and led to increased frequencies of primary cilia, they unexpectedly reduced the levels of aaTub in the cilia. To test whether the antiproliferative effects of HDAC6 inhibitors are dependent on tumor cell cilia, we generated patient-derived glioma lines devoid of cilia through depletion of ciliogenesis genes ARL13B or KIF3A. At low concentrations, 1215 or 738 did not decrease the proliferation of cilia-depleted cells. Moreover, the differentiation of glioma cells that was induced by HDAC6 inhibition did not occur after the inhibition of cilia formation. These data suggest HDAC6 signaling at primary cilia promotes the proliferation of glioma cells by restricting their ability to differentiate. Surprisingly, overexpressing HDAC6 did not reduce cilia length or the frequency of ciliated glioma cells, suggesting other factors are required to control HDAC6-mediated cilia disassembly in glioma cells. Collectively, our findings suggest that HDAC6 promotes the proliferation of glioma cells through primary cilia.

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