HDAC1,2 inhibition impairs EZH2- and BBAP- mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma

Johnson, Danielle P.; Spitz, Gabriella S.; Tharkar, Shweta; Quayle, Steven N.; Shearstone, Jeffrey R.; Jones, Simon; McDowell, Maria E.; Wellman, Hannah; Tyler, Jessica K.; Cairns, Bradley R.; Chandrasekharan, Mahesh B.; Bhaskara, Srividya

doi:10.18632/oncotarget.3120

Cited by 35 publications

(50 citation statements)

References 62 publications

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“…Although there is often high responsiveness at first, the majority of patients eventually progress to platinum-resistant disease. HDAC1 expression is associated with drug resistance in several cancers [10,11,13,33,34]. Cacan et al [11].…”

Section: Discussionmentioning

confidence: 99%

HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response

Liu

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cisplatin-based treatment is first-line chemotherapy for several cancers including ovarian cancer. The development of cisplatin resistance results in treatment failure, but the underlying mechanisms are not fully understood. Histone deacetylases (HDACs) are a large family of enzymes that deacetylate lysine residues on histones and non-histone proteins. High expression of HDAC1 is associated with poor outcomes in ovarian cancer. Furthermore, resistance to chemotherapeutic agents is associated with HDAC1 overexpression in ovarian cancer cells. The goals of this study were to determine whether targeting HDAC1 can sensitize ovarian cancer cells to cisplatin and to explore the underlying mechanisms. Methods: Small interfering RNA (siRNA)-targeting HDAC1 was designed to silence HDAC1 in the cisplatin-resistant ovarian cancer cell line A2780^CDDP and its cisplatin-sensitive cell line A2780. The effects of targeting HDAC1 on cell viability assay, colony formation, and apoptosis were detected. c-Myc re-expression or miR-34a inhibitors were used to examine the relationship among HDAC1, c-Myc, and miR-34a expression, which was assessed by western blot analysis and quantitative reverse transcription PCR. We established stable transfectants of A2780^CDDP/HDAC1 short hairpin RNA (shRNA) and A2780/HDAC1 shRNA. The therapeutic effectiveness of cisplatin in murine xenograft models was assessed following shRNA-mediated HDAC1 silencing in A2780^CDDP and A2780 cells. The mechanism of cell death was studied in tumor sections obtained from different mouse tumors. Results: In cisplatin-resistant A2780^CDDP cells, HDAC1 knockdown by siRNA suppressed cell proliferation, and increased apoptosis and chemosensitivity by downregulating c-Myc and upregulating miR-34a. In cisplatin-sensitive A2780 cells, HDAC1 knockdown did not affect cell proliferation and apoptosis. Cisplatin treatment activated HDAC1 and c-Myc and inactivated miR-34a. Inhibition of HDAC1 with siRNA reduced c-Myc expression, increased miR-34a expression, and sensitized A2780 cells to cisplatin-induced apoptosis. c-Myc re-expression or miR-34a targeting by miR-34a inhibitors protected cells from apoptosis or reversed cisplatin resistance following HDAC1 knockdown or/and cisplatin exposure. Finally, in vivo studies showed that targeting HDAC1 inhibited A2780^CDDP-induced xenograft tumor growth but not A2780-induced xenograft tumor growth. Targeting HDAC1 sensitized both A2780- and A2780^CDDP-induced xenograft tumors to cisplatin treatment. Conclusions: Upregulation of HDAC1 is a crucial event in the development of drug resistance to current treatments in ovarian cancer. Thus, targeting HDAC1 by enhancing c-Myc-dependent miR-34a expression might be an effective strategy for increasing the efficacy of cisplatin treatment.

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Section: Discussionmentioning

confidence: 99%

HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response

Liu

Zhang

et al. 2018

Cell Physiol Biochem

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“…26 Previous studies showed that hyperacetylation induced by sodium butyrate stimulates nucleotide excision repair in UVirradiated cells. 8,10,[47][48][49][50] The stimulation of DNA repair was shown to be associated with alterations in chromatin structure making damaged sites in DNA more accessible to repair enzymes. Moreover, impaired chromatin relaxation observed in the presence of the HAT inhibitor garcinol, suppressed the NHEJ pathway in DSBs repair 36 .…”

Section: Discussionmentioning

confidence: 99%

Acetylation regulates DNA repair mechanisms in human cells

2016

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The p300-mediated acetylation of enzymes involved in DNA repair and replication has been previously shown to stimulate or inhibit their activities in reconstituted systems. To explore the role of acetylation on DNA repair in cells we constructed plasmid substrates carrying inactivating damages in the EGFP reporter gene, which should be repaired in cells through DNA mismatch repair (MMR) or base excision repair (BER) mechanisms. We analyzed efficiency of repair within these plasmid substrates in cells exposed to deacetylase and acetyltransferase inhibitors, and also in cells deficient in p300 acetyltransferase. Our results indicate that protein acetylation improves DNA mismatch repair in MMR-proficient HeLa cells and also in MMR-deficient HCT116 cells. Moreover, results suggest that stimulated repair of mismatches in MMR-deficient HCT116 cells is done though a strand-displacement synthesis mechanism described previously for Okazaki fragments maturation and also for the EXOI-independent pathway of MMR. Loss of p300 reduced repair of mismatches in MMR-deficient cells, but did not have evident effects on BER mechanisms, including the long patch BER pathway. Hypoacetylation of the cells in the presence of acetyltransferase inhibitor, garcinol generally reduced efficiency of BER of 8-oxoG damage, indicating that some steps in the pathway are stimulated by acetylation.

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“…HDAC1 and 2, which are exclusively found in the nucleus of cells as they do not contain a nuclear export signal (108,109), deacetylate acetylated lysine 56 of histone 3 (H3K56Ac) (110,111) and acetylated lysine 16 of histone 4 (H4K16Ac) (110) (Figure 1C). In addition, inhibition of HDAC1 and 2 increases acetylation of histone 4 at lysine 91 (H4K91Ac) (112) (Figure 1C). Decreased H3K56Ac, H4K16Ac and H4K91Ac deacetylation due to the lack of or inhibition of, HDAC1 and 2 were paralleled by decreased survival of cells upon the induction of DSBs (110,112), and HDAC1 and 2 could, therefore, promote DSB repair by removing histone marks at DSBs.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, inhibition of HDAC1 and 2 increases acetylation of histone 4 at lysine 91 (H4K91Ac) (112) (Figure 1C). Decreased H3K56Ac, H4K16Ac and H4K91Ac deacetylation due to the lack of or inhibition of, HDAC1 and 2 were paralleled by decreased survival of cells upon the induction of DSBs (110,112), and HDAC1 and 2 could, therefore, promote DSB repair by removing histone marks at DSBs. The PcG polycomb repressive complex 1 (PRC1) contributes to the ubiquitination of histone H2A following the induction of DSBs (103,113–115).…”

Section: Introductionmentioning

confidence: 99%

The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair

Roos¹,

Krumm²

2016

Nucleic Acids Res

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Histone/protein deacetylases play multiple roles in regulating gene expression and protein activation and stability. Their deregulation during cancer initiation and progression cause resistance to therapy. Here, we review the role of histone deacetylases (HDACs) and the NAD+ dependent sirtuins (SIRTs) in the DNA damage response (DDR). These lysine deacetylases contribute to DNA repair by base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end joining (NHEJ), homologous recombination (HR) and interstrand crosslink (ICL) repair. Furthermore, we discuss possible mechanisms whereby these histone/protein deacetylases facilitate the switch between DNA double-strand break (DSB) repair pathways, how SIRTs play a central role in the crosstalk between DNA repair and cell death pathways due to their dependence on NAD+, and the influence of small molecule HDAC inhibitors (HDACi) on cancer cell resistance to genotoxin based therapies. Throughout the review, we endeavor to identify the specific HDAC targeted by HDACi leading to therapy sensitization.

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HDAC1,2 inhibition impairs EZH2- and BBAP- mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma

Cited by 35 publications

References 62 publications

HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response

HDAC1 Silencing in Ovarian Cancer Enhances the Chemotherapy Response

Acetylation regulates DNA repair mechanisms in human cells

The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair

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