scholarly journals Co-regulation and function of FOXM1/RHNO1 bidirectional genes in cancer

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Carter J Barger ◽  
Linda Chee ◽  
Mustafa Albahrani ◽  
Catalina Munoz-Trujillo ◽  
Lidia Boghean ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Human Cancer ◽  
Parp Inhibitor ◽  
Bidirectional Promoter ◽  
Serous Carcinoma ◽  
Therapeutic Targeting ◽  
Recombination Repair ◽  
Dna Replication Stress ◽  
And Function ◽  
Inhibitor Resistance

The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the most common and lethal form of human ovarian cancer, and is linked to copy number gains at chromosome 12p13.33. We show that FOXM1 is co-amplified and co-expressed with RHNO1, a gene involved in the ATR-Chk1 signaling pathway that functions in the DNA replication stress (RS) response. We demonstrate that FOXM1 and RHNO1 are head-to-head (i.e. bidirectional) genes (BDG) regulated by a bidirectional promoter (BDP) (named F/R-BDP). FOXM1 and RHNO1 each promote oncogenic phenotypes in HGSC cells, including clonogenic growth, DNA homologous recombination repair (HR), and poly-ADP ribosylase (PARP) inhibitor resistance. FOXM1 and RHNO1 are one of the first examples of oncogenic BDG, and therapeutic targeting of FOXM1/RHNO1 BDG is a potential therapeutic approach for ovarian and other cancers.

scholarly journals Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer

2019 ◽  
Author(s):  
Carter J Barger ◽  
Connor Branick ◽  
Linda Chee ◽  
Mustafa Albahrani ◽  
David Klinkebiel ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Human Cancer ◽  
Single Cells ◽  
Clonogenic Survival ◽  
Bidirectional Promoter ◽  
Recombination Repair ◽  
Dna Replication Stress ◽  
Cancer Tissues ◽  
Oncogenic Transcription Factor ◽  
Bidirectional Gene Pair

SummaryWe report that the oncogenic transcription factorFOXM1is arranged in a head-to-head configuration withRHNO1, a gene involved in the ATR/CHK1-dependent DNA replication stress (DRS) response.FOXM1andRHNO1are both amplified and upregulated in high-grade serous ovarian cancer (HGSC).FOXM1andRHNO1expression are closely associated in normal and cancer tissues, including single cells, and a bidirectional promoter (F/R-BDP) mediates balanced expression. Targeting of FOXM1 and RHNO1 in HGSC cells using shRNA, CRISPR mutagenesis, or CRISPR interference directed to the F/R-BDP reduced DNA homologous recombination repair (HR) capacity, increased DNA damage, reduced clonogenic survival, and sensitized HGSC cells to the poly-ADP ribosylase inhibitor (PARPi) olaparib. Thus, there is functional cooperativity between FOXM1 and RHNO1 in cancer cells, and combinatorial targeting of this bidirectional gene pair may be a novel cancer therapeutic strategy. More broadly, our data provide evidence that bidirectional gene units function in human cancer.

Loss of Nuclear DNA Ligase III Reverts PARP Inhibitor Resistance in BRCA1-Deficient Cells by Increasing DNA Replication Stress

2020 ◽  
Author(s):  
Mariana Paes Dias ◽  
Vivek Tripathi ◽  
Ingrid van der Heijden ◽  
Ke Cong ◽  
Eleni-Maria Manolika ◽  
...  
Keyword(s):  
Dna Replication ◽  
Nuclear Dna ◽  
Parp Inhibitor ◽  
Replication Stress ◽  
Dna Ligase ◽  
Dna Replication Stress ◽  
Inhibitor Resistance ◽  
Dna Ligase Iii

scholarly journals Identifying and Overcoming Mechanisms of PARP Inhibitor Resistance in Homologous Recombination Repair-Deficient and Repair-Proficient High Grade Serous Ovarian Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1503
Author(s):  
Miriam K. Gomez ◽  
Giuditta Illuzzi ◽  
Carlota Colomer ◽  
Michael Churchman ◽  
Robert L. Hollis ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Parp Inhibitor ◽  
Homologous Recombination Repair ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Strand Breaks ◽  
G2 Checkpoint ◽  
Recombination Repair ◽  
Wee1 Kinase ◽  
Inhibitor Resistance

High grade serous ovarian cancer (HGSOC) is a major cause of female cancer mortality. The approval of poly (ADP-ribose) polymerase (PARP) inhibitors for clinical use has greatly improved treatment options for patients with homologous recombination repair (HRR)-deficient HGSOC, although the development of PARP inhibitor resistance in some patients is revealing limitations to outcome. A proportion of patients with HRR-proficient cancers also benefit from PARP inhibitor therapy. Our aim is to compare mechanisms of resistance to the PARP inhibitor olaparib in these two main molecular categories of HGSOC and investigate a way to overcome resistance that we considered particularly suited to a cancer like HGSOC, where there is a very high incidence of TP53 gene mutation, making HGSOC cells heavily reliant on the G2 checkpoint for repair of DNA damage and survival. We identified alterations in multiple factors involved in resistance to PARP inhibition in both HRR-proficient and -deficient cancers. The most frequent change was a major reduction in levels of poly (ADP-ribose) glycohydrolase (PARG), which would be expected to preserve a residual PARP1-initiated DNA damage response to DNA single-strand breaks. Other changes seen would be expected to boost levels of HRR of DNA double-strand breaks. Growth of all olaparib-resistant clones isolated could be controlled by WEE1 kinase inhibitor AZD1775, which inactivates the G2 checkpoint. Our work suggests that use of the WEE1 kinase inhibitor could be a realistic therapeutic option for patients that develop resistance to olaparib.

scholarly journals RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer

2018 ◽  
Vol 29 (5) ◽  
pp. 1203-1210 ◽  
Author(s):  
C. Cruz ◽  
M. Castroviejo-Bermejo ◽  
S. Gutiérrez-Enríquez ◽  
A. Llop-Guevara ◽  
Y.H. Ibrahim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Homologous Recombination Repair ◽  
Recombination Repair ◽  
Inhibitor Resistance

scholarly journals Loss of Nuclear DNA ligase III Can Revert PARP Inhibitor Resistance in BRCA1-deficient Cells by Increasing DNA Replication Stress

2021 ◽  
Author(s):  
Mariana Paes Dias ◽  
Vivek Tripathi ◽  
Ingrid van der Heijden ◽  
Ke Cong ◽  
Eleni-Maria Manolika ◽  
...  
Keyword(s):  
Nuclear Dna ◽  
Chromosomal Abnormalities ◽  
Parp Inhibitor ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Replication Forks ◽  
Genetic Screens ◽  
Dna Replication Stress ◽  
Inhibitor Resistance

SUMMARYInhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1, identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 is required for PARPi-induced fork acceleration in BRCA1-deficient cells and that LIG3 loss increases fork asymmetry. Furthermore, LIG3 depletion in BRCA1-deficient cells results in an increase in ssDNA gaps behind the replication forks, resulting in accumulation of chromosomal abnormalities. We also report that high expression of LIG3 in patients with invasive breast cancer correlates in with poorer overall survival, rendering LIG3 as a potential therapeutic target for enhancing PARPi sensitivity.

scholarly journals REV7/FANCV Binds to CHAMP1 and Promotes Homologous Recombination Repair

2021 ◽  
Author(s):  
Feng Li ◽  
Prabha Sarangi ◽  
Hanrong Feng ◽  
Lisa Moreau ◽  
Huy Nguyen ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Dna Double Strand Breaks ◽  
Critical Determinant ◽  
Strand Breaks ◽  
Positive Regulator ◽  
Recombination Repair ◽  
Nhej Repair ◽  
Inhibitor Resistance

A critical determinant of DNA repair pathway choice is the HORMA protein REV7, a small abundant adaptor which binds to various DNA repair proteins through its C-terminal seatbelt domain. The REV7 seatbelt binds to the REV3 polymerase to form the Polymerase ζ complex, a positive regulator of translesion synthesis (TLS) repair. Alternatively, the REV7 seatbelt binds to SHLD3 in the Shieldin complex, a positive regulator of NHEJ repair. Recent studies have identified another novel REV7 seatbelt-binding protein, CHAMP1 (Chromosome Alignment-Maintaining Phosphoprotein, though its role in DNA repair is unknown. Here, we show that the REV7-CHAMP1 complex promotes homologous recombination (HR) repair by sequestering REV7 from the Shieldin complex. CHAMP1 competes directly with the SHLD3 subunit of the Shieldin complex for a limited pool of C-REV7, thereby inhibiting the REV7-mediated recruitment of the SHLD2 and SHLD1 effector subunits to DNA double strand breaks. CHAMP1 thereby channels DNA repair away from error-prone NHEJ and towards the competing error-free HR pathway. Similarly, CHAMP1 competes with the REV3 component of the POLζ complex, thereby reducing the level of mutagenic TLS repair. CHAMP1 interacts with POGZ in a heterochromatin complex further promoting HR repair. Importantly, in human tumors, CHAMP1 overexpression promotes HR, confers PARP inhibitor resistance, and correlates with poor prognosis. Thus, by binding to either REV3, SHLD3, or CHAMP1 through its seatbelt, the REV7 protein can promote either TLS repair, NHEJ repair, or HR repair respectively.

A Mucin-Specific Protease Enables Molecular and Functional Analysis of Human Cancer-Associated Mucins

2018 ◽  
Author(s):  
Stacy A. Malaker ◽  
Kayvon Pedram ◽  
Michael J. Ferracane ◽  
Elliot C. Woods ◽  
Jessica Kramer ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
High Resolution Mass Spectrometry ◽  
Human Cancer ◽  
Glycosylation Sites ◽  
Bacterial Protease ◽  
Specific Protease ◽  
To Come ◽  
And Function

<div> <div> <div> <p>Mucins are a class of highly O-glycosylated proteins that are ubiquitously expressed on cellular surfaces and are important for human health, especially in the context of carcinomas. However, the molecular mechanisms by which aberrant mucin structures lead to tumor progression and immune evasion have been slow to come to light, in part because methods for selective mucin degradation are lacking. Here we employ high resolution mass spectrometry, polymer synthesis, and computational peptide docking to demonstrate that a bacterial protease, called StcE, cleaves mucin domains by recognizing a discrete peptide-, glycan-, and secondary structure- based motif. We exploited StcE’s unique properties to map glycosylation sites and structures of purified and recombinant human mucins by mass spectrometry. As well, we found that StcE will digest cancer-associated mucins from cultured cells and from ovarian cancer patient-derived ascites fluid. Finally, using StcE we discovered that Siglec-7, a glyco-immune checkpoint receptor, specifically binds sialomucins as biological ligands, whereas the related Siglec-9 receptor does not. Mucin-specific proteolysis, as exemplified by StcE, is therefore a powerful tool for the study of glycoprotein structure and function and for deorphanizing mucin-binding receptors. </p> </div> </div> </div>

scholarly journals 1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer

2021 ◽  
Vol 7 (4) ◽  
pp. eabe1174
Author(s):  
Marisa K. Kilgour ◽  
Sarah MacPherson ◽  
Lauren G. Zacharias ◽  
Abigail E. Ellis ◽  
Ryan D. Sheldon ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Modulation ◽  
Human Cancer ◽  
Serous Carcinoma ◽  
Necrosis Factor Alpha ◽  
Methyl Group ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Alpha ◽  
Immunotherapy Target ◽  
Necrosis Factor

Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few exceptions, their identities remain largely unknown. Here, we profiled tumor and T cells from tumor and ascites of patients with high-grade serous carcinoma (HGSC) to uncover the metabolomes of these distinct TME compartments. Cells within the ascites and tumor had pervasive metabolite differences, with a notable enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared with ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the enzyme that catalyzes the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Functionally, MNA induces T cells to secrete the tumor-promoting cytokine tumor necrosis factor alpha. Thus, TME-derived MNA contributes to the immune modulation of T cells and represents a potential immunotherapy target to treat human cancer.

scholarly journals Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Yiqing Cai ◽  
Rui Feng ◽  
Tiange Lu ◽  
Xiaomin Chen ◽  
Xiangxiang Zhou ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Human Cancer ◽  
Rna Modification ◽  
Rapid Progression ◽  
Antitumor Therapy ◽  
Promoting Effect ◽  
Methyl Group ◽  
Group Transfer ◽  
Functional Regulation ◽  
Methyl Group Transfer

AbstractN6-methyladenosine (m6A) is a prevalent internal RNA modification in higher eukaryotic cells. As the pivotal m6A regulator, RNA methyltransferase-like 3 (METTL3) is responsible for methyl group transfer in the progression of m6A modification. This epigenetic regulation contributes to the structure and functional regulation of RNA and further promotes tumorigenesis and tumor progression. Accumulating evidence has illustrated the pivotal roles of METTL3 in a variety of human cancers. Here, we systemically summarize the interaction between METTL3 and RNAs, and illustrate the multiple functions of METTL3 in human cancer. METLL3 is aberrantly expressed in a variety of tumors. Elevation of METTL3 is usually associated with rapid progression and poor prognosis of tumors. On the other hand, METTL3 may also function as a tumor suppressor in several cancers. Based on the tumor-promoting effect of METTL3, the possibility of applying METTL3 inhibitors is further discussed, which is expected to provide novel insights into antitumor therapy.

scholarly journals Overview of Inositol and Inositol Phosphates on Chemoprevention of Colitis-Induced Carcinogenesis

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 31
Author(s):  
Samuel E. Weinberg ◽  
Le Yu Sun ◽  
Allison L. Yang ◽  
Jie Liao ◽  
Guang Yu Yang
Keyword(s):  
Inositol Phosphates ◽  
Human Cancer ◽  
Energy Transduction ◽  
Nutritional Deficiencies ◽  
Increased Risk ◽  
Rna Export ◽  
Inflammatory Bowel ◽  
And Function ◽  
Biologic Function ◽  
Atp Regeneration

Chronic inflammation is one of the most common and well-recognized risk factors for human cancer, including colon cancer. Inflammatory bowel disease (IBD) is defined as a longstanding idiopathic chronic active inflammatory process in the colon, including ulcerative colitis and Crohn’s disease. Importantly, patients with IBD have a significantly increased risk for the development of colorectal carcinoma. Dietary inositol and its phosphates, as well as phospholipid derivatives, are well known to benefit human health in diverse pathologies including cancer prevention. Inositol phosphates including InsP3, InsP6, and other pyrophosphates, play important roles in cellular metabolic and signal transduction pathways involved in the control of cell proliferation, differentiation, RNA export, DNA repair, energy transduction, ATP regeneration, and numerous others. In the review, we highlight the biologic function and health effects of inositol and its phosphates including the nature and sources of these molecules, potential nutritional deficiencies, their biologic metabolism and function, and finally, their role in the prevention of colitis-induced carcinogenesis.

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