HDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype by promoting radioresistance in glioblastoma cells

Marampon, Francesco; Megiorni, Francesca; Camero, Simona; Crescioli, Clara; McDowell, Heather P.; Sferra, Roberta; Vetuschi, Antonella; Pompili, Simona; Ventura, Laura; Felice, Francesca De; Tombolini, Vincenzo; Dominici, Carlo; Maggio, Roberto; Festuccia, Claudio; Gravina, Giovanni Luca

doi:10.1016/j.canlet.2017.03.028

Cited by 81 publications

(69 citation statements)

References 50 publications

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“…16,23 Highly expressed HDAC4 is positively correlated with the tumor grade and negatively correlated with overall survival rates. 40,41 Recently, HDAC4-mediated transcriptional suppression of p21 expression has been found to contribute to malignant proliferation of gliomas, 23 as well as other cancer cells, including breast cancer, 42 colon cancer 43 and lung adenocarcinoma, 44 implying that HDAC4 nuclear import is most likely predominant due to its role in tumorigenesis. Through IHC analysis, we found that the rates of nuclear HDAC4 significantly increased among Grade II, III and Grade IV glioma samples and were positively correlated with the grades.…”

Section: Discussionmentioning

confidence: 99%

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Wang

Xia

et al. 2019

Intl Journal of Cancer

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JNK activity has been implicated in the malignant proliferation, invasion and drug‐resistance of glioma cells (GCs), but the molecular mechanisms underlying JNK activation are currently unknown. Here, we reported that MKK7, not MKK4, directly activates JNK in GCs and exerts oncogenic effects on tumor formation. Notably, MKK7 expression in glioma tissues was closely correlated with the grade of the glioma and JNK/c‐Jun activation. Mechanistically, MKK7 transcription critically depends on the complexes formed by HDAC4 and the transcriptional factors SP1 and Krüppel‐like factor‐5 (KLF5), wherein HDAC4 directly deacetylates both SP1 and KLF5 and synergistically upregulates MKK7 transcription through two SP1 sites located on its promoter. In contrast, the increases in acetylated‐SP1 and acetylated‐KLF5 after HDAC4 inhibition switched to transcriptionally suppress MKK7. Selective inhibition of HDAC4 by LMK235, siRNAs or blockage of SP1 and KLF5 by the ectopic dominant‐negative SP1 greatly reduced the malignant capacity of GCs. Furthermore, suppression of both MKK7 expression and JNK/c‐Jun activities was involved in the tumor‐growth inhibitory effects induced by LMK235 in U87‐xenograft mice. Interestingly, HDAC4 is highly expressed in glioma tissues, and the rate of HDAC4 nuclear import is closely correlated with glioma grade, as well as with MKK7 expression. Collectively, these findings demonstrated that highly expressed MKK7 contributes to JNK/c‐Jun signaling‐mediated glioma formation. MKK7 transcription, regulated by SP1 and KLF5, critically depends on HDAC4 activity, and inhibition of HDAC4 presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c‐Jun signaling in GCs.

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Section: Discussionmentioning

confidence: 99%

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Wang

Xia

et al. 2019

Intl Journal of Cancer

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Section: Introductionmentioning

confidence: 99%

“…Histone deacetylase 4 (HDAC4) plays global roles in the regulation of gene transcription, cell growth, survival and proliferation, and their aberrant expressions or activities contribute to cancer development. [5][6][7][8][9][10] Zeng LS revealed that upregulated HDAC4 is associated with higher tumor grade, advanced clinical stage, and poor survival rate in esophageal carcinoma, also they found that HDAC4 promoted proliferation and G1/S cell cycle progression in EC cells. 11 Vallabhapurapu | 4585 SUN aNd QIN SD demonstrated that HDAC4 and its downstream complex maintained repressive chromatin around pro-apoptotic genes Bim and BMF and regulates multiple myeloma (MM) survival and growth.…”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNA MALAT1 regulates HDAC4‐mediated proliferation and apoptosis via decoying of miR‐140‐5p in osteosarcoma cells

Sun

Qin

2018

Cancer Medicine

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Noncoding RNAs regulate the initiation and progression of osteosarcoma (OS). The role of long noncoding RNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) playing in OS and whether the function it working out was achieved through HDAC4 pathway remain uncovered. In this study, we illustrated that MALAT1 was upregulated and was correlated with poor prognosis in OS patients. Meanwhile, we demonstrated that a depression of MALAT1 suppressed proliferation and promoted apoptosis in OS cell line HOS and 143B. Further, we verified that MALAT1 exerting its function via upregulating of histone deacetylase 4 (HDAC4). Through an online prediction, a series of luciferase assays and RNA pull‐down assays, we demonstrated that both MALAT1 and HDAC4 were the targets of microRNA‐140‐5p (miR‐140‐5p) via sharing a similar microRNA responding elements. Even further, we revealed that MALAT1 served as a ceRNA of HDAC4 via decoying of miR‐140‐5p. Finally, we proved that MALAT1 promoted OS tumor growth in an in vivo animal study. In summary, the outcomes of this study demonstrated the complex ceRNA network among MALAT, miR‐140‐5p, and HDAC4‐mediated proliferation and apoptosis in OS. This study might provide a new axial in molecular treatment of OS.

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“…Hence, the induction of DNA damage and TP53 activation seems to involve different pathways compared with the replication stress induced by RAS. Previous reports have described correlations between HDAC4 and the DNA damage response, and also with TP53 regulation (Cadot et al ., ; Marampon et al ., ). Unfortunately, these preliminary observations have not led to further studies and currently the correlations between class IIa HDACs and the DNA damage response remain unknown.…”

Section: Discussionmentioning

confidence: 97%

Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53‐dependent senescence and favors cell transformation

2018

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Expression of the class IIa HDACs is frequently altered in different human cancers. In mouse models these transcriptional repressors can trigger transformation, acting as bona fide oncogenes. Whether class IIa HDACs also exhibit transforming activities in human cells is currently unknown. We infected primary human fibroblasts with retroviruses to investigate the transforming activity of HDAC4 in cooperation with well‐known oncogenes. We have discovered that HDAC4 triple mutant (S246A, S467A, S632A) (HDAC4‐TM), a nuclear resident version of the deacetylase, triggers TP53 stabilization and OIS (oncogene‐induced senescence). Unlike RAS, HDAC4‐induced OIS was TP53‐dependent and characterized by rapid cell cycle arrest and accumulation of an unusual pattern of γH2AX‐positive foci. The inactivation of both TP53 and of the retinoblastoma (pRb) tumor suppressors, as induced by the viral oncogenes large and small T of SV40, triggers anchorage‐independent growth in RAS, HDAC4‐TM and, to a lesser extent, in HDAC4‐wild type (WT)‐expressing cells. Our results suggest an oncogenic function of class IIa HDACs in human cells, and justify further efforts to discover and evaluate isoform‐specific inhibitors of these epigenetic regulators from a therapeutic perspective.

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HDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype by promoting radioresistance in glioblastoma cells

Cited by 81 publications

References 50 publications

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Long noncoding RNA MALAT1 regulates HDAC4‐mediated proliferation and apoptosis via decoying of miR‐140‐5p in osteosarcoma cells

Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53‐dependent senescence and favors cell transformation

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