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Uc.454 Inhibited Growth by Targeting Heat Shock Protein Family A Member 12B in Non-Small-Cell Lung Cancer.

ABSTRACT: Transcribed ultraconserved regions (T-UCRs) classified as long non-coding RNAs (Lnc-RNAs) are transcripts longer than 200-nt RNA with no protein-coding capacity. Previous studies showed that T-UCRs serve as novel oncogenes, or tumor suppressors are involved in tumorigenesis and cancer progressive. Nevertheless, the clinicopathologic significance and regulatory mechanism of T-UCRs in lung cancer (LC) remain largely unknown. We found that uc.454 was downregulated in both non-small-cell LC (NSCLC) tissues and LC cell lines, and the downregulated uc.454 is associated with tumor size and tumors with more advanced stages. Transfection with uc.454 markedly induced apoptosis and inhibited cell proliferation in SPC-A-1 and NCI-H2170 LC cell lines. Above results suggested that uc.454 played a suppressive role in LC. Heat shock protein family A member 12B (HSPA12B) protein was negatively regulated by uc.454 at the posttranscriptional level by dual-luciferase reporter assay and affected the expressions of Bcl-2 family members, which finally induced LC apoptosis. The uc.454/HSPA12B axis furthers our understanding of the molecular mechanisms involved in tumor apoptosis, which may potentially serve as a therapeutic target for lung carcinoma.

SUBMITTER: Zhou J

PROVIDER: S-EPMC6023848 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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uc.454 Inhibited Growth by Targeting Heat Shock Protein Family A Member 12B in Non-Small-Cell Lung Cancer.

Zhou Jun J Wang Chenghai C Gong Weijuan W Wu Yandan Y Xue Huimin H Jiang Zewei Z Shi Minhua M

Molecular therapy. Nucleic acids 20180529

Transcribed ultraconserved regions (T-UCRs) classified as long non-coding RNAs (Lnc-RNAs) are transcripts longer than 200-nt RNA with no protein-coding capacity. Previous studies showed that T-UCRs serve as novel oncogenes, or tumor suppressors are involved in tumorigenesis and cancer progressive. Nevertheless, the clinicopathologic significance and regulatory mechanism of T-UCRs in lung cancer (LC) remain largely unknown. We found that uc.454 was downregulated in both non-small-cell LC (NSCLC) ...[more]

PMID: 30195756

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Project description:Hepatitis B virus (HBV) contains a partially double-stranded relaxed circular DNA (rcDNA) genome that is converted into a covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocyte by cellular DNA repair machinery. cccDNA associates with nucleosomes to form a minichromosome that transcribes RNA to support the expression of viral proteins and reverse transcriptional replication of viral DNA. In addition to the de novo synthesis from incoming virion rcDNA, cccDNA can also be synthesized from rcDNA in the progeny nucleocapsids within the cytoplasm of infected hepatocytes via the intracellular amplification pathway. In our efforts to identify cellular DNA repair proteins required for cccDNA synthesis using a chemogenetic screen, we found that B02, a small-molecule inhibitor of DNA homologous recombination repair protein RAD51, significantly enhanced the synthesis of cccDNA via the intracellular amplification pathway in human hepatoma cells. Ironically, neither small interfering RNA (siRNA) knockdown of RAD51 expression nor treatment with another structurally distinct RAD51 inhibitor or activator altered cccDNA amplification. Instead, it was found that B02 treatment significantly elevated the levels of multiple heat shock protein mRNA, and siRNA knockdown of HSPA1 expression or treatment with HSPA1 inhibitors significantly attenuated B02 enhancement of cccDNA amplification. Moreover, B02-enhanced cccDNA amplification was efficiently inhibited by compounds that selectively inhibit DNA polymerase α or topoisomerase II, the enzymes required for cccDNA intracellular amplification. Our results thus indicate that B02 treatment induces a heat shock protein-mediated cellular response that positively regulates the conversion of rcDNA into cccDNA via the authentic intracellular amplification pathway. IMPORTANCE Elimination or functional inactivation of cccDNA minichromosomes in HBV-infected hepatocytes is essential for the cure of chronic hepatitis B virus (HBV) infection. However, lack of knowledge of the molecular mechanisms of cccDNA metabolism and regulation hampers the development of antiviral drugs to achieve this therapeutic goal. Our findings reported here imply that enhanced cccDNA amplification may occur under selected pathobiological conditions, such as cellular stress, to subvert the dilution or elimination of cccDNA and maintain the persistence of HBV infection. Therapeutic inhibition of HSPA1-enhanced cccDNA amplification under these pathobiological conditions should facilitate the elimination of cccDNA and cure of chronic hepatitis B.

Project description:BackgroundIn living organisms, small heat shock proteins (sHSPs) are triggered in response to stress situations. This family of proteins is large in plants and, in the case of tomato (Solanum lycopersicum), 33 genes have been identified, most of them related to heat stress response and to the ripening process. Transcriptomic and proteomic studies have revealed complex patterns of expression for these genes. In this work, we investigate the coregulation of these genes by performing a computational analysis of their promoter architecture to find regulatory motifs known as heat shock elements (HSEs). We leverage the presence of sHSP members that originated from tandem duplication events and analyze the promoter architecture diversity of the whole sHSP family, focusing on the identification of HSEs.ResultsWe performed a search for conserved genomic sequences in the promoter regions of the sHSPs of tomato, plus several other proteins (mainly HSPs) that are functionally related to heat stress situations or to ripening. Several computational analyses were performed to build multiple sequence motifs and identify transcription factor binding sites (TFBS) homologous to HSF1AE and HSF21 in Arabidopsis. We also investigated the expression and interaction of these proteins under two heat stress situations in whole tomato plants and in protoplast cells, both in the presence and in the absence of heat shock transcription factor A2 (HsfA2). The results of these analyses indicate that different sHSPs are up-regulated depending on the activation or repression of HsfA2, a key regulator of HSPs. Further, the analysis of protein-protein interaction between the sHSP protein family and other heat shock response proteins (Hsp70, Hsp90 and MBF1c) suggests that several sHSPs are mediating alternative stress response through a regulatory subnetwork that is not dependent on HsfA2.ConclusionsOverall, this study identifies two regulatory motifs (HSF1AE and HSF21) associated with the sHSP family in tomato which are considered genomic HSEs. The study also suggests that, despite the apparent redundancy of these proteins, which has been linked to gene duplication, tomato sHSPs showed different up-regulation and different interaction patterns when analyzed under different stress situations.

Project description:Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological conditions associated with the human host and in the arthropod vectors requires the parasites to modulate their metabolic complement in order to meet the prevailing conditions. One of the key features of these parasites essential for their survival and host infectivity is timely expression of various proteins. Even more importantly is the need to keep their proteome functional by maintaining its functional capabilities in the wake of physiological changes and host immune responses. For this reason, molecular chaperones (also called heat shock proteins)-whose role is to facilitate proteostasis-play an important role in the survival of these parasites. Heat shock protein 90 (Hsp90) and Hsp70 are prominent molecular chaperones that are generally induced in response to physiological stress. Both Hsp90 and Hsp70 members are functionally regulated by nucleotides. In addition, Hsp70 and Hsp90 cooperate to facilitate folding of some key proteins implicated in cellular development. In addition, Hsp90 and Hsp70 individually interact with other accessory proteins (co-chaperones) that regulate their functions. The dependency of these proteins on nucleotide for their chaperone function presents an Achille's heel, as inhibitors that mimic ATP are amongst potential therapeutic agents targeting their function in obligate intracellular human parasites. Most of the promising small molecule inhibitors of parasitic heat shock proteins are either antibiotics or anticancer agents, whose repurposing against parasitic infections holds prospects. Both cancer cells and obligate human parasites depend upon a robust protein quality control system to ensure their survival, and hence, both employ a competent heat shock machinery to this end. Furthermore, some inhibitors that target chaperone and co-chaperone networks also offer promising prospects as antiparasitic agents. The current review highlights the progress made so far in design and application of small molecule inhibitors against obligate intracellular human parasites of the kinetoplastida and apicomplexan kingdoms.

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Uc.454 Inhibited Growth by Targeting Heat Shock Protein Family A Member 12B in Non-Small-Cell Lung Cancer.

Publications

uc.454 Inhibited Growth by Targeting Heat Shock Protein Family A Member 12B in Non-Small-Cell Lung Cancer.

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