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Rlip Depletion Alters Oncogene Transcription at Multiple Distinct Regulatory Levels.

ABSTRACT: Rlip76 (Rlip) is a multifunctional membrane protein that facilitates the high metabolic rates of cancer cells through the efflux of toxic metabolites and other functions. Rlip inhibition or depletion results in broad-spectrum anti-cancer effects in vitro and in vivo. Rlip depletion effectively suppresses malignancy and causes global reversion of characteristic CpG island methylomic and transcriptomic aberrations in the p53-null mouse model of spontaneous carcinogenesis through incompletely defined signaling and transcriptomic mechanisms. The methylome and transcriptome are normally regulated by the concerted actions of several mechanisms that include chromatin remodeling, promoter methylation, transcription factor interactions, and miRNAs. The present studies investigated the interaction of Rlip depletion or inhibition with the promoter methylation and transcription of selected cancer-related genes identified as being affected by Rlip depletion in our previous studies. We constructed novel promoter CpG island/luciferase reporter plasmids that respond only to CpG methylation and transcription factors. We found that Rlip depletion regulated expression by a transcription factor-based mechanism that functioned independently of promoter CpG methylation, lipid peroxidation, and p53 status.

SUBMITTER: Hindle A

PROVIDER: S-EPMC8833773 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Rlip Depletion Alters Oncogene Transcription at Multiple Distinct Regulatory Levels.

Hindle Ashly A Bose Chhanda C Lee Jihyun J Palade Philip T PT Peterson Christopher J CJ Reddy P Hemachandra PH Awasthi Sanjay S Singh Sharda P SP

Cancers 20220121 3

Rlip76 (Rlip) is a multifunctional membrane protein that facilitates the high metabolic rates of cancer cells through the efflux of toxic metabolites and other functions. Rlip inhibition or depletion results in broad-spectrum anti-cancer effects in vitro and in vivo. Rlip depletion effectively suppresses malignancy and causes global reversion of characteristic CpG island methylomic and transcriptomic aberrations in the p53-null mouse model of spontaneous carcinogenesis through incompletely defin ...[more]

PMID: 35158795

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Project description:Although high-grade serous ovarian cancer (OVC) is the most lethal gynecologic malignancy in women, little is known about the regulatory mechanisms in the cellular processes that lead to this cancer. Recently, accumulated lines of evidence have shown that the interplay between transcription factors (TFs) and microRNAs (miRNAs) is critical in cellular regulation during tumorigenesis. A comprehensive investigation of TFs and miRNAs, and their target genes, may provide a deeper understanding of the regulatory mechanisms in the pathology of OVC. In this study, we have integrated three complementary algorithms into a framework, aiming to infer the regulation by miRNAs and TFs in conjunction with gene expression profiles. We demonstrated the utility of our framework by inferring 67 OVC-specific regulatory feed-forward loops (FFL) initiated by miRNAs or TFs in high-grade serous OVC. By analyzing these regulatory behaviors, we found that all the 67 FFLs are consistent in their regulatory effects on genes that are jointly targeted by miRNAs and TFs. Remarkably, we unveiled an unbalanced distribution of FFLs with different oncogenic effects. In total, 31 of the 67 coherent FFLs were mainly initiated by oncogenes. On the contrary, only 4 of the FFLs were initiated by tumor suppressor genes. These overwhelmingly observed oncogenic genes were further detected in a sub-network with 32 FFLs centered by miRNA let-7b and TF TCF7L1 to regulate cell differentiation. Closer inspection of 32 FFLs revealed that 75% of the miRNAs reportedly play functional roles in cell differentiation, especially when enriched in epithelial-mesenchymal transitions. This study provides a comprehensive pathophysiological overview of recurring coherent circuits in OVC that are co-regulated by miRNAs and TFs. The prevalence of oncogenic coherent FFLs in serous OVC suggests that oncogene-driven regulatory motifs could cooperatively act upon critical cellular processes such as cell differentiation in a highly efficient and consistent manner.

Dataset Information

Rlip Depletion Alters Oncogene Transcription at Multiple Distinct Regulatory Levels.

Publications

Rlip Depletion Alters Oncogene Transcription at Multiple Distinct Regulatory Levels.

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