Aberrant Regulation of HDAC2 Mediates Proliferation of Hepatocellular Carcinoma Cells by Deregulating Expression of G1/S Cell Cycle Proteins

Noh, Ji Heon; Jung, Kwang Hwa; Kim, Jeong Kyu; Eun, Jung Woo; Bae, Hyun Jin; Xie, Hong; Chang, Young Gyoon; Kim, Min; Park, Won Sang; Lee, Jung Young; Nam, Suk Woo

doi:10.1371/journal.pone.0028103

Cited by 83 publications

(79 citation statements)

References 28 publications

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“…Our data show that in fact lamin A/C binds the CDKN1A promoter and the interaction between lamin A/C and HDAC2 favors HDAC2 recruitment (Noh et al, 2011), as suggested by reduced deacetylase binding in HGPS, despite increased protein levels.…”

Section: Discussionsupporting

confidence: 66%

“…It was demonstrated (Peng et al, 2015) that HDAC2 is recruited to CDKN1A promoter by FOXO3a and regulates p21 expression in cerebellar granule neuron. Furthermore, HDAC2 has been shown to suppress p21 expression in human hepatocellular carcinoma via its binding to an Sp1‐binding site (Noh et al, 2011). On the other hand, it has been demonstrated that lamin A/C establishes direct interactions with histone deacetylases including SIRT1 (Cenni et al, 2014; Liu et al, 2012), SIRT6 (Ghosh, Liu, Wang, Hao, & Zhou, 2015), and HDAC1 (Kubben et al, 2016), while lamin partners at the nuclear envelope such as emerin, BAF, and LAP2beta interact with HDAC3 (Demmerle, Koch, & Holaska, 2013) or HDAC2 (Tsai et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson–Gilford progeria, a severe LMNA‐linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C‐HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C‐HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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“…We recently reported that aberrant expression (highly expressed) of HDAC2 in hepatocellular carcinomas and its mitogenic functions are associated with the transcriptional regulations of cell-cycle regulators (7). To generalize our findings, we examined HDAC2 gene expressional data in a large cohort of patients with hepatocellular carcinoma, available from the NCBIGEO database (accession numbers GSE14520, GSE16757, and GSE25097).…”

Section: Resultsmentioning

confidence: 90%

“…S1C). In addition, we performed GSEA using three different cancer cell lines (liver, lung, and gastric cancer) to confirm HDAC2 signatures in these cell lines (7,9,10). Indeed, GSEA showed that EGFR system-related gene elements were commonly enriched in HDAC2 signatures observed in these cell lines (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Our previous studies suggested that overexpression of HDAC2 plays a pivotal role in the development of hepatocellular carcinoma due to its regulation of cell-cycle components at the transcription levels (7). However, the underlying mechanisms linking HDAC2 and hepatocellular malignant progression and transformation have not been determined.…”

Section: Introductionmentioning

confidence: 99%

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HDAC2 Provides a Critical Support to Malignant Progression of Hepatocellular Carcinoma through Feedback Control of mTORC1 and AKT

et al. 2014

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Aberrant regulation of histone deacetylase 2 (HDAC2) contributes to malignant progression in various cancers, but the underlying mechanism leading to the activation of oncogenic HDAC2 remains unknown. In this study, we show that HDAC2 expression is upregulated in a large cohort of patients with human hepatocellular carcinoma, and that high expression of HDAC2 was significantly associated with poor prognosis of patients with hepatocellular carcinoma. We found that mTORC1/NF-kBp50 signaling is necessary for the growth factorinduced HDAC2 and is sustained in hepatocellular carcinoma, but not in normal hepatic cells. Growth factorinduced mTORC1 activates the nuclear translocation of NF-kBp50, where it binds to the intragenic sequences of the HDAC2 gene and promotes its transcription. Hepatocellular carcinoma tissues derived from chemicalinduced mouse and rat liver cancer models validated that mTORC1 activation and NF-kBp50 nuclear translocation are essential for the transcriptional activation of oncogenic HDAC2 in hepatocellular carcinoma. In addition, we demonstrate that HDAC2 is required to maintain mTORC1 activity by stabilizing the mTOR/ RAPTOR complex. Elevated expression of HDAC2 triggers a positive feedback loop that activates AKT phosphorylation via the transcriptional modulation of phosphoinositide signaling molecules. Bioinformatics analysis of HDAC2 signature and immunoblot analysis of mesenchymal genes also evidenced that HDAC2 plays a role in the malignant behavior of tumor cells by Snail induction and simultaneously E-cadherin suppression in hepatocellular carcinoma cells. These findings establish a molecular mechanism responsible for the activation of oncogenic HDAC2, which explains how growth factor-induced HDAC2 maintains mitogenic signaling and function during hepatocellular malignant progression and provide a novel strategy for therapeutic intervention in liver cancer. Cancer Res; 74(6); 1728-38. Ó2014 AACR.

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Loss of histone deacetylases 1 and 2 in hepatocytes impairs murine liver regeneration through Ki67 depletion

Xia

Zhou²,

Ji³

et al. 2013

Hepatology

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Histone deacetylases 1 and 2 (HDAC1 and HDAC2) are ubiquitously expressed in tissues, including the liver, and play critical roles in numerous physiopathological processes. Little is known regarding the role of HDAC1 and HDAC2 in liver regeneration. In this study we generated mice in which Hdac1, Hdac2 or both genes were selectively knocked out in hepatocytes to investigate the role of these genes in liver regeneration following hepatic injury induced by partial hepatectomy or carbon tetrachloride administration. The loss of HDAC1 and/or HDAC2 (HDAC1/2) protein resulted in impaired liver regeneration. HDAC1/2 inactivation did not decrease hepatocytic 5-bromo-2-deoxyuridine uptake or the expression of proliferating cell nuclear antigen, cyclins, or cyclin-dependent kinases. However, the levels of Ki67, a mitotic marker that is expressed from the mid-G 1 phase to the end of mitosis and is closely involved in the regulation of mitotic progression, were greatly decreased, and abnormal mitosis lacking Ki67 expression was frequently observed in HDAC1/2-deficient livers. The down-regulation of either HDAC1/2 or Ki67 in the mouse liver cancer cell line Hepa1-6 resulted in similar mitotic defects. Finally, both HDAC1 and HDAC2 proteins were associated with the Ki67 gene mediated by CCAAT/enhancer-binding protein b. Conclusion: Both HDAC1 and HDAC2 play crucial roles in the regulation of liver regeneration. The loss of HDAC1/2 inhibits Ki67 expression and results in defective hepatocyte mitosis and impaired liver regeneration. (HEPATOLOGY 2013;58:2089-2098

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Aberrant Regulation of HDAC2 Mediates Proliferation of Hepatocellular Carcinoma Cells by Deregulating Expression of G1/S Cell Cycle Proteins

Cited by 83 publications

References 28 publications

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

HDAC2 Provides a Critical Support to Malignant Progression of Hepatocellular Carcinoma through Feedback Control of mTORC1 and AKT

Loss of histone deacetylases 1 and 2 in hepatocytes impairs murine liver regeneration through Ki67 depletion

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