Histone posttranslational modifications represent a versatile set of epigenetic marks involved not only in dynamic cellular processes, such as transcription and DNA repair, but also in the stable maintenance of repressive chromatin. In this article, we review many of the key and newly identified histone modifications known to be deregulated in cancer and how this impacts function. The latter part of the article addresses the challenges and current status of the epigenetic drug development process as it applies to cancer therapeutics.

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Histone Modifications and Cancer.

Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence. Epigenetic dysregulation is often linked to human disease, notably cancer. With the development of various drugs targeting epigenetic regulators, epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials. In this review, we summarize the aberrant functions of enzymes in DNA methylation, histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.

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Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.

Lung cancer stem cells: The root of resistance.

Lung cancer is one of the most frequent cancer types and the leading cause of cancer death worldwide. Cisplatin is a widely used chemotherapeutic for non-small cell lung carcinoma (NSCLC), however, its positive effects are diminished under hypoxia. We wanted to determine if co-treatment with cisplatin and histone deacetalyse (HDAC) inhibitor panobinostat can reduce hypoxia-induced cisplatin resistance in NSCLC cells, and to elucidate mechanism involved. Expression status of different HDACS was determined in two cell lines and in tumor tissue from 20 patients. Cells were treated with cisplatin, panobinostat, or with combination of both under normoxic and hypoxic (1% O2) conditions. Cell cycle, viability, acetylation of histones, and activation of apoptosis were determined. HIF-1α stability and its interaction with HDAC4 were analyzed. Most class I and II HDACs were expressed in NSCLC cells and tumor samples. Co-treatment of tumor cells with cisplatin and panobinostat decreased cell viability and increased apoptosis more efficiently than in primary, non-malignant bronchial epithelial cells. Co-treatment induced apoptosis by causing chromatin fragmentation, activation of caspases-3 and 7 and PARP cleavage. Toxic effects were more pronounced under hypoxic conditions. Co-treatment resulted in destabilization and degradation of HIF-1α and HDAC4, a protein responsible for acetylation and de/stabilization of HIF-1α. Direct interaction between HDAC4 and HIF-1α proteins in H23 cells was detected. Here we show that hypoxia-induced cisplatin resistance can be overcome by combining cisplatin with panobinostat, a potent HDAC inhibitor. These findings may contribute to the development of a new therapeutic strategy for NSCLC.

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Panobinostat reduces hypoxia-induced cisplatin resistance of non-small cell lung carcinoma cells via HIF-1α destabilization

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children under the age of 15. In addition to genetic aberrations, epigenetic modifications such as DNA methylation are altered in cancer and impact gene expression. To identify epigenetic alterations in ALL, genome-wide methylation profiles were generated using the methylated CpG island recovery assay followed by next-generation sequencing. More than 25,000 differentially methylated regions (DMR) were observed in ALL patients with ∼90% present within intronic or intergenic regions. To determine the regulatory potential of the DMR, whole-transcriptome analysis was performed and integrated with methylation data. Aberrant promoter methylation was associated with the altered expression of genes involved in transcriptional regulation, apoptosis, and proliferation. Novel enhancer-like sequences were identified within intronic and intergenic DMR. Aberrant methylation in these regions was associated with the altered expression of neighborin...

https://www.tandfonline.com/doi/pdf/10.1080/15592294.2015.1078050

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia.

Our previous studies identified important molecules involved in lung carcinogenesis through a comprehen - sive search for the downstream targets of oncogenic KRAS, and these findings suggested that an investigation into the downstream targets of oncogenic KRAS might represent a useful strategy for elucidating the common molecular bases of lung cancer. Among the downstream targets of oncogenic KRAS, a focus was placed on HDAC9, a mem- ber of the histone deacetylase family, in the present study because epigenetic modification of DNA or the histone proteins is known to play an important role in carcinogenesis. The immunohistochemical expression of HDAC9 was examined in surgically resected primary lung cancers (130 adenocarcinoma, 49 squamous cell carcinomas, one large cell carcinoma, and 6 small cell carcinomas) and potential associations between its expression level and pathologic factors were analyzed. The results showed that HDAC9 expression levels were lower in lung cancer cells than in non-tumor epithelial cells, and were also significantly lower in adenocarcinomas among the histological types. Moreover, HDAC9 expression levels were significantly lower in adenocarcinomas with lymphatic canal involve - ment. The restoration of HDAC9 in lung cancer cells losing its expression severely attenuated their growth activity in vitro. These results suggest that HDAC9 may be a suppressor and its downregulation might promote the progression process, especially in lung adenocarcinomas.

Original Article Expression of HDAC9 in lung cancer - potential role in lung carcinogenesis

There could be two carcinogenetic pathways for lung adenocarcinoma (LADC), that are, the non-smokers' pathway and the smokers' pathway. This review article describes the two pathways with special reference to potential relationships between histological subtypes, malignant grades, and driver mutations. The lung is composed of two different tissue units, the terminal respiratory unit (TRU) and the central airway compartment (CAC). In the non-smokers' pathway, LADCs develop from the TRU, and their histological appearances change from lepidic to micropapillary during the progression process. In the smokers' pathway, LADCs develop from either the TRU or the CAC, and their histological appearances vary among cases in the middle of the progression process, but they are likely converged to acinar/solid at the end. On a molecular genetic level, the non-smokers' pathway is mostly driven by EGFR mutations, whereas in the smokers' pathway, approximately one-quarter of LADCs have KRAS mutations, but the other three-quarters have no known driver mutations. p53 mutations are an important factor triggering the progression of both pathways, with unique molecular alterations associated with each, such as MUC21 expression, chromosome 12p13-21 amplification in the non-smokers' pathway, and HNF4α expression and TTF1 mutations in the smokers' pathway. However, investigation into the relationship between histological progression and genetic alterations is in its infancy. Tight cooperation between traditional histopathological examinations and recent molecular genetics can provide valuable insight into better understanding the nature of LADCs.

The nonsmokers' and smokers' pathways in lung adenocarcinoma: Histological progression and molecular bases.

Received October 4, 2012; Accepted November 1, 2012; Epub November 20, 2012; Published January 1, 2013Abstract: ALDH1A1 metabolizes a variety of endogenous and exogenous aldehyde, and also oxidizes retinol to synthesize retinoic acid and modulate cell differentiation. Moreover, ALDH1A1 is also suggested to participate in the maintenance of cancer stem cells. To investigate the potential role of ALDH1A1 in carcinogenesis of the lung, the present study examined two hundred and sixty eight cases of non-small cell lung carcinoma (NSCLC) for its immunohistochemical expression and analyzed associations between ALDH1A1 levels and a series of clinicopatho -logic parameters. Also, the biological significance of the aberrant expression of ALDH1A1 was investigated in vitro. ALDH1A1 expression was markedly reduced in 39.9% (107/268) of NSCLCs. The incidence of this reduction was significantly higher in adenocarcinomas (ADC: 41.6%, 85/207) and large cell carcinomas (61.1%, 11/18) than squamous cell carcinomas (25.5%, 11/43). Among ADCs, the downregulation tended to be more remarkable in high grade, poorly differentiated tumors, and tumors with stronger proliferating activity. It also occurred with a sig-nificantly higher incidence in smokers than non-smokers. Forced expression of ALDH1A1 in NSCLC cell lines, which had lost ALDH1A1 expression, markedly attenuated their growth. Taken together, loss of ALDH1A1 expression is suggested to promote carcinogenesis especially in the smoking-related ADCs. Keywords: Non-small cell lung carcinoma, ALDH1A1, immunohistochemistry, tumor suppressor, smoking, cancer stem cell

Tetsukan Woo

Papers

Original Article Expression of HDAC9 in lung cancer - potential role in lung carcinogenesis

The nonsmokers' and smokers' pathways in lung adenocarcinoma: Histological progression and molecular bases.

Original Article Downregulation of ALDH1A1 expression in non-small cell lung carcinomas - its clinicopathologic and biological significance