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

Barger, Carter J.; Chee, Linda; Albahrani, Mustafa; Muñoz-Trujillo, Catalina; Boghean, Lidia; Branick, Connor; Odunsi, Kunle; Drapkin, Ronny; Zou, Lee; Karpf, Adam R.

doi:10.7554/elife.55070

Cited by 22 publications

(13 citation statements)

References 138 publications

(249 reference statements)

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“…In HGSC patients, shallow whole genome sequencing (sWGS) of circulating tumor DNA (ctDNA) from plasma revealed a 16% increase in chromosome 12p13.33 amplification (location of FOXM1 ) after the acquisition of chemotherapy resistance [ 128 ]. In agreement, we observed that almost half of HGSC patients have increased FOXM1 expression in recurrent chemoresistant tumors [ 256 ]. Bioinformatic analysis led to the identification of FOXM1 as one of the top three hub genes for which overexpression leads to platinum-based chemotherapy resistance [ 257 ].…”

Section: Foxm1 Oncogenic Functionssupporting

confidence: 77%

“…We showed that RHNO1 , which encodes a DNA damage repair protein involved in the cellular RS response, shares a head-to-head (i.e., bidirectional) gene arrangement with FOXM1 on chromosome 12p13.33 [ 256 ]. Activation of the FOXM1/RHNO1 bidirectional promoter (F/R-BDP) leads to balanced gene expression of both genes and we observed that FOXM1 and RHNO1 each promote HGSC cell growth, survival, and homologous recombination (HR) DNA damage repair [ 256 ]. Importantly, FOXM1 and RHNO1 promoted olaparib and carboplatin resistance, and CRISPR-dCas9-mediated repression of the F/R-BDP reversed these effects [ 256 ].…”

Section: Foxm1 Oncogenic Functionsmentioning

confidence: 99%

“…Activation of the FOXM1/RHNO1 bidirectional promoter (F/R-BDP) leads to balanced gene expression of both genes and we observed that FOXM1 and RHNO1 each promote HGSC cell growth, survival, and homologous recombination (HR) DNA damage repair [ 256 ]. Importantly, FOXM1 and RHNO1 promoted olaparib and carboplatin resistance, and CRISPR-dCas9-mediated repression of the F/R-BDP reversed these effects [ 256 ]. We postulate that cancer cells have a selective advantage for FOXM1 and RHNO1 co-expression since FOXM1 drives RS and downstream oncogenic phenotypes such as genomic instability, while RHNO1 helps mitigate FOXM1-induced RS to a level more favorable to cancer cell survival.…”

Section: Foxm1 Oncogenic Functionsmentioning

confidence: 99%

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FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

Liu

Barger

Karpf

2021

Cancers

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Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment.

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Section: Foxm1 Oncogenic Functionssupporting

confidence: 77%

Section: Foxm1 Oncogenic Functionsmentioning

confidence: 99%

Section: Foxm1 Oncogenic Functionsmentioning

confidence: 99%

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FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

Liu

Barger

Karpf

2021

Cancers

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“…To investigate the potential use of the NB compounds in combination with relevant HGSC chemotherapies, we investigated the synergy between NB-73 or NB-115 with the platinum-based chemotherapy agent carboplatin or the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. Combinations with these chemotherapy agents are supported by the known role of FOXM1 in stimulating the expression of DNA repair genes 8 as well as our recent studies using genetic depletions of FOXM1 44 .…”

Section: Nb-73 and Nb-115 Synergize With Carboplatin To Impair Hgsc C...mentioning

confidence: 91%

New 1,1-diarylethylene FOXM1 inhibitors potently reduce intracellular FOXM1 and suppress high-grade serous ovarian carcinoma cell viability

Liu

Muñoz-Trujillo

Kim

et al. 2022

Preprint

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As an oncogenic transcription factor highly upregulated in numerous cancer types and responsible for promoting multiple hallmarks of the disease, Forkhead Box M1 (FOXM1) is a promising target for treatment against high-grade ovarian serous carcinoma (HGSC), a lethal and aggressive cancer that overexpresses FOXM1 and its transcriptional pathway. Several FOXM1 inhibitors have been established, but none have advanced to clinical trials. In this study, we report that our recently developed 1,1-diarylethylene FOXM1 inhibitors (NB compounds) potently and selectively inhibit HGSC cell viability, more so than a panel of other reported FOXM1 inhibitors. The NB compounds decreased FOXM1 expression through proteasomal degradation, which resulted in decreased expression of its downstream target cyclin B1 (CCNB1), without affecting other FOX family members. Moreover, the NB compounds exhibited robust anti-cancer effects by promoting apoptosis, suppressing colony formation more potently than other FOXM1 inhibitors, and synergizing with carboplatin to inhibit the viability of HGSC cells. Our data demonstrate that the NB compounds are promising FOXM1 inhibitors that may serve as a novel therapeutic strategy for HGSC and other cancers whose aggressive cancer biology is driven by FOXM1 and its oncogenic transcriptional pathway.

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“…Forkhead box M1 (FOXM1) is a transcription factor and a target of HuR [23], and overexpression and activation of FOXM1 is frequent and associated with worse prognosis in patients with HGSOC [24,25]. Moreover, FOXM1 overexpression also contributes to cell proliferation, cell cycle progression, chemoresistance, migration, and invasion in HGSOC [25][26][27].…”

Section: Foxm1 Which Is Regulated By Hur Contributes To the Anti-hgso...mentioning

confidence: 99%

SOCS7/HuR/FOXM1 signaling axis inhibited high-grade serous ovarian carcinoma progression

et al. 2022

J Exp Clin Cancer Res

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Background High-grade serous ovarian carcinoma (HGSOC) is clinically dominant and accounts for ~ 80% deaths in all types of ovarian cancer. The delayed diagnosis, rapid development, and wide dissemination of HGSOC collectively contribute to its high mortality rate and poor prognosis in the patients. Suppressors of cytokine signaling 7 (SOCS7) can regulate cytokine signaling and participate in cell cycle arrest and regulation of cell proliferation, which might also be involved in carcinogenesis. Here, we designated to investigate the functions and mechanisms of SOCS7 in HGSOC. Methods The clinical correlation between SOCS7 and HGSOC was examined by both bioinformatics and analysis of tissue samples in patients. Gain/Loss-of-function examinations were carried out to assess the effectiveness of SOCS7 in cell viability, cell cycle, and tumor growth of HGSOC. Furthermore, the underlying mechanisms were explored by identifying the downstream proteins and their interactions via proteomics analysis and immunoprecipitation. Results The expression of SOCS7, which was decreased in HGSOC tissues, was correlated with the clinical pathologic characteristics and overall survival of HGSOC patients. SOCS7 acted as a HGSOC suppressor by inhibiting cancer cell viability and tumor growth in vivo. The anti-HGSOC mechanism involves SOCS7’s regulatory effect on HuR by mediating its ubiquitination, the regulation of FOXM1 mRNA by HuR, as well as the interplays among these three clinically relevant factors. Conclusions The SOCS7 correlates with HGSOC and suppresses its tumorigenesis through regulating HuR and FOXM1, which also suggests that SOCS7 is a prospective biomarker for the clinical management of ovarian cancer, especially HGSOC.

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

Cited by 22 publications

References 138 publications

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

New 1,1-diarylethylene FOXM1 inhibitors potently reduce intracellular FOXM1 and suppress high-grade serous ovarian carcinoma cell viability

SOCS7/HuR/FOXM1 signaling axis inhibited high-grade serous ovarian carcinoma progression

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