Epigenetic Regulation of Autophagy Beyond the Cytoplasm: A Review

Autophagy is a highly conserved catabolic process induced under various stress conditions to protect the cell from harm and allow survival in the face of nutrient- or energy-deficient states. Regulation of autophagy is complex, as cells need to adapt to a continuously changing microenvironment. It is well recognized that the AMPK and mTOR signaling pathways are the main regulators of autophagy. However, various other signaling pathways have also been described to regulate the autophagic process. A better understanding of these complex autophagy regulatory mechanisms will allow the discovery of new potential therapeutic targets. Here, we present a brief overview of autophagy and its regulatory pathways with emphasis on the epigenetic control mechanisms.

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The Multifaceted Roles of USP15 in Signal Transduction

International Journal of Molecular Sciences ◽

10.3390/ijms22094728 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4728

Author(s):

Tanuza Das ◽

Eun Joo Song ◽

Eunice EunKyeong Kim

Keyword(s):

Signal Transduction ◽

Signaling Pathways ◽

Cellular Networks ◽

Clinical Applications ◽

Regulatory Mechanisms ◽

Signaling Networks ◽

Post Translational Modification ◽

Comprehensive Overview ◽

E3 Ligases ◽

Disease Markers

Ubiquitination and deubiquitination are protein post-translational modification processes that have been recognized as crucial mediators of many complex cellular networks, including maintaining ubiquitin homeostasis, controlling protein stability, and regulating several signaling pathways. Therefore, some of the enzymes involved in ubiquitination and deubiquitination, particularly E3 ligases and deubiquitinases, have attracted attention for drug discovery. Here, we review recent findings on USP15, one of the deubiquitinases, which regulates diverse signaling pathways by deubiquitinating vital target proteins. Even though several basic previous studies have uncovered the versatile roles of USP15 in different signaling networks, those have not yet been systematically and specifically reviewed, which can provide important information about possible disease markers and clinical applications. This review will provide a comprehensive overview of our current understanding of the regulatory mechanisms of USP15 on different signaling pathways for which dynamic reverse ubiquitination is a key regulator.

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Inhibition Effect of Chloroquine and Integrin-Linked Kinase Knockdown on Translation in Melanoma Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22073682 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3682

Author(s):

Dorota Gil ◽

Piotr Laidler ◽

Marta Zarzycka ◽

Joanna Dulińska-Litewka

Keyword(s):

Signaling Pathways ◽

Melanoma Cell ◽

Melanoma Cells ◽

Antitumor Effects ◽

Regulatory Pathways ◽

Scratch Wound ◽

Integrin Linked Kinase ◽

And Migration ◽

Cell Signaling Pathways

The twofold role of autophagy in cancer is often the therapeutic target. Numerous regulatory pathways are shared between autophagy and other molecular processes needed in tumorigenesis, such as translation or survival signaling. Thus, we have assumed that ILK knockdown should promote autophagy, and used together with chloroquine, an autophagy inhibitor, it could generate a better anticancer effect by dysregulation of common signaling pathways. Expression at the protein level was analyzed using Western Blot; siRNA transfection was done for ILK. Analysis of cell signaling pathways was monitored with phospho-specific antibodies. Melanoma cell proliferation was assessed with the crystal violet test, and migration was evaluated by scratch wound healing assays. Autophagy was monitored by the accumulation of its marker, LC3-II. Our data show that ILK knockdown by siRNA suppresses melanoma cell growth by inducing autophagy through AMPK activation, and simultaneously initiates apoptosis. We demonstrated that combinatorial treatment of melanoma cells with CQ and siILK has a stronger antitumor effect than monotherapy with either of these. It generates the synergistic antitumor effects by the decrease of translation of both global and oncogenic proteins synthesis. In our work, we point to the crosstalk between translation and autophagy regulation.

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11-epi-Sinulariolide Acetate Reduces Cell Migration and Invasion of Human Hepatocellular Carcinoma by Reducing the Activation of ERK1/2, p38MAPK and FAK/PI3K/AKT/mTOR Signaling Pathways

Marine Drugs ◽

10.3390/md12094783 ◽

2014 ◽

Vol 12 (9) ◽

pp. 4783-4798 ◽

Cited By ~ 22

Author(s):

Jen-Jie Lin ◽

Jui-Hsin Su ◽

Chi-Chu Tsai ◽

Yi-Jen Chen ◽

Ming-Hui Liao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Migration ◽

Signaling Pathways ◽

Mtor Signaling ◽

Human Hepatocellular Carcinoma ◽

Migration And Invasion ◽

Cell Migration And Invasion

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AKIP1 promotes cell proliferation, invasion, stemness and activates PI3K-Akt, MEK/ERK, mTOR signaling pathways in prostate cancer

10.21203/rs.3.rs-568302/v1 ◽

2021 ◽

Author(s):

Jiabin Zhao ◽

Binjiahui Zhao ◽

Limin Hou

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Signaling Pathways ◽

Cancer Patients ◽

Rna Sequencing ◽

Mtor Signaling ◽

Sequencing Analysis ◽

Lncap Cells ◽

Oncogenic Signaling ◽

Interacting Protein

Abstract Background: The study aimed to examine the molecular mechanism and clinical significance of A-kinase interacting protein 1 (AKIP1) in prostate cancer. Methods: The effect of AKIP1 on cell proliferation, migration, invasion, apoptosis and stemness was determined by overexpressing and knocking down AKIP1 in LNCaP and 22Rv1 cells via lentivirus infection. Furthermore, differentially expressed genes (DEGs) by AKIP1 modification were determined using RNA sequencing. Besides, the correlation of AKIP1 with clinicopathological features and prognosis in 130 prostate cancer patients was assessed. Results: AKIP1 expression was increased in VCaP, LNCaP, DU145 cells while similar in 22Rv1 cells compared with RWPE-1 cells. Furthermore, AKIP1 overexpression promoted 22Rv1 and LNCaP cell proliferation, invasion, but inhibited apoptosis; meanwhile, AKIP1 overexpression increased CD133+ cell rate and enhanced spheres formation efficiency in 22Rv1 and LNCaP cells. Reversely, AKIP1 knockdown exhibited the opposite effect in 22Rv1 and LNCaP cells. Further RNA sequencing analysis exhibited that AKIP1-modified DEGs were enriched in the oncogenic signaling pathways related to prostate cancer, such as PI3K-Akt, MEK/ERK, mTOR signaling pathways. The following western blot indicated that AKIP1 overexpression activated while its knockdown blocked PI3K-Akt, MEK/ERK, mTOR signaling pathways in prostate cancer cells. Clinically, AKIP1 was upregulated in the prostate tumor tissues compared with paired adjacent tissues, and its tumor high expression correlated with increased pathological T, pathological N stage and poor prognosis in prostate cancer patients. Conclusion: AKIP1 promotes cell proliferation, invasion, stemness, activates PI3K-Akt, MEK/ERK, mTOR signaling pathways and correlates with worse tumor features and prognosis in prostate cancer.

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Gene therapy can target mutations such as BRAF, which have been shown to make tumors more susceptible to autophagy suppression

10.31219/osf.io/3gwra ◽

2021 ◽

Author(s):

Moataz Dowaidar

Keyword(s):

Signaling Pathways ◽

Chemotherapy Resistance ◽

Effective Strategy ◽

Cell Type ◽

Normal Cells ◽

A Cell ◽

Cell Type Specific ◽

Catabolic Process ◽

Specific Impact

Autophagy is a double-edged sword in cancer, and numerous aspects should be taken into account before deciding on the most effective strategy to target the process. The fact that several clinical studies are now ongoing does not mean that the patient group that may benefit from autophagy-targeting medicines has been identified. Autophagy inhibitors that are more potent and specialized, as well as autophagy indicators, are also desperately required. The fact that these inhibitors only work against tumors that rely on autophagy for survival (RAS mutants) makes it difficult to distinguish them from tumors that continue to develop even when autophagy is absent. Furthermore, mutations such as BRAF have been shown to make tumors more susceptible to autophagy suppression, suggesting that targeting such tumours may be a viable strategy for overcoming their chemotherapy resistance. In the meantime, we are unable to identify if autophagy regulation works in vivo or whether it selectively targets a disease while inflicting injury to other healthy organs and tissues. A cell-type-specific impact appears to be observed with such therapy. As a result, it is just as important to consider the differences between tumors that originate in different organs as it is to consider the signaling pathways that are similar across them. For a therapy or cure to be effective, the proposed intervention must be tailored to the specific needs of each patient.Over the last several years, a growing amount of data has implicated autophagy in a variety of disorders, including cancer. In normal cells, this catabolic process is also required for cell survival and homeostasis. Despite the fact that medications targeting intermediates in the autophagy signaling pathway are being created and evaluated at both the preclinical and clinical levels, given the complicated function of autophagy in cancer, we still have a long way to go in terms of establishing an effective therapeutic approach. This article discusses current tactics for exploiting cancer cells' autophagy dependency, as well as obstacles in the area. We believe that the unanswered concerns raised in this work will stimulate researchers to investigate previously unknown connections between autophagy and other signaling pathways, which might lead to the development of novel, highly specialized autophagy therapies.

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Sulfated polysaccharide of Sepiella Maindroni ink inhibits the migration, invasion and matrix metalloproteinase-2 expression through suppressing EGFR-mediated p38/MAPK and PI3K/Akt/mTOR signaling pathways in SKOV-3 cells

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2017.08.178 ◽

2018 ◽

Vol 107 ◽

pp. 349-362 ◽

Cited By ~ 12

Author(s):

Wenjie Jiang ◽

Yanna Cheng ◽

Na Zhao ◽

Lian Li ◽

Yikang Shi ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Signaling Pathways ◽

P38 Mapk ◽

Sulfated Polysaccharide ◽

Mtor Signaling ◽

Matrix Metalloproteinase 2 ◽

Sepiella Maindroni

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Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion

Journal of Applied Physiology ◽

10.1152/japplphysiol.01122.2005 ◽

2006 ◽

Vol 101 (2) ◽

pp. 576-582 ◽

Cited By ~ 14

Author(s):

Stephen J. Crozier ◽

Xueqian Zhang ◽

Jufang Wang ◽

Joseph Cheung ◽

Scot R. Kimball ◽

...

Keyword(s):

Protein Kinase ◽

Myocardial Ischemia ◽

Protein Expression ◽

Signaling Pathways ◽

Mrna Translation ◽

Mitogen Activated Protein Kinase ◽

Regulatory Mechanisms ◽

Ischemia And Reperfusion ◽

Myocardial Ischemia And Reperfusion ◽

Mitogen Activated Protein

Protein expression in the heart is altered following periods of myocardial ischemia. The changes in protein expression are associated with increased cell size that can be maladaptive. There is little information regarding the regulation of protein expression through the process of mRNA translation during ischemia and reperfusion in the heart. Therefore, the purpose of this study was to identify changes in signaling pathways and downstream regulatory mechanisms of mRNA translation in an in vivo model of myocardial ischemia and reperfusion. Hearts were collected from rats whose left main coronary arteries had either been occluded for 25 min or reversibly occluded for 25 min and subsequently reperfused for 15 min. Following reperfusion, both the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways were activated, as evidenced by increased phosphorylation of Akt (PKB), extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase. Activation of Akt stimulated signaling through the protein kinase mammalian target of rapamycin, as evidenced by increased phosphorylation of two of its effectors, the ribosomal protein S6 kinase and the eukaryotic initiation factor eIF4E binding protein 1. Ischemia and reperfusion also resulted in increased phosphorylation of eIF2 and eIF2B. These changes in protein phosphorylation suggest that control of mRNA translation following ischemia and reperfusion is modulated through a number of signaling pathways and regulatory mechanisms.

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Epigenetic regulation by the menin pathway

Endocrine Related Cancer ◽

10.1530/erc-17-0298 ◽

2017 ◽

Vol 24 (10) ◽

pp. T147-T159 ◽

Cited By ~ 15

Author(s):

Zijie Feng ◽

Jian Ma ◽

Xianxin Hua

Keyword(s):

Transcription Factors ◽

Cell Signaling ◽

Signaling Pathways ◽

Gene Transcription ◽

Epigenetic Regulation ◽

Posttranslational Modifications ◽

Genetic Model ◽

Mirna Biogenesis ◽

Endocrine Organs

There is a trend of increasing prevalence of neuroendocrine tumors (NETs), and the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome serves as a genetic model to investigate how NETs develop and the underlying mechanisms. Menin, encoded by the MEN1 gene, at least partly acts as a scaffold protein by interacting with multiple partners to regulate cellular homeostasis of various endocrine organs. Menin has multiple functions including regulation of several important signaling pathways by controlling gene transcription. Here, we focus on reviewing the recent progress in elucidating the key biochemical role of menin in epigenetic regulation of gene transcription and cell signaling, as well as posttranslational regulation of menin itself. In particular, we will review the progress in studying structural and functional interactions of menin with various histone modifiers and transcription factors such as MLL, PRMT5, SUV39H1 and other transcription factors including c-Myb and JunD. Moreover, the role of menin in regulating cell signaling pathways such as TGF-beta, Wnt and Hedgehog, as well as miRNA biogenesis and processing will be described. Further, the regulation of the MEN1 gene transcription, posttranslational modifications and stability of menin protein will be reviewed. These various modes of regulation by menin as well as regulation of menin by various biological factors broaden the view regarding how menin controls various biological processes in neuroendocrine organ homeostasis.

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