APOBEC: A molecular driver in cervical cancer pathogenesis

Abstract

Cervical cancer is one of the foremost common cancers in women. Human papillomavirus (HPV) infection remains a major risk factor of cervical cancer. In addition, numerous other genetic and epigenetic factors also are involved in the underlying pathogenesis of cervical cancer. Recently, it has been reported that apolipoprotein B mRNA editing enzyme catalytic polypeptide like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. Particularly, the APOBEC3 family was shown to induce tumor mutations by aberrant DNA editing mechanism. In general, APOBEC3 enzymes play a pivotal role in the deamination of cytidine to uridine in DNA and RNA to control diverse biological processes such as regulation of protein expression, innate immunity, and embryonic development. Innate antiviral activity of the APOBEC3 family members restrict retroviruses, endogenous retro-element, and DNA viruses including the HPV that is the leading risk factor for cervical cancer. This review briefly describes the pathogenesis of cervical cancer and discusses in detail the recent findings on the role of APOBEC in the molecular pathogenesis of cervical cancer.

HPV Meets APOBEC: New Players in Head and Neck Cancer

“…Thus, there has been an increasing interest in determining whether altered expression profiles of APOBECs in tumor cells can increase the occurrence of somatic mutations. This may be in part supported by recent findings showing that germline variations of APOBECs are associated with increased mutagenic capacity, which then may promote tumorigenesis [ 39 ]. In this regard, whole exome and genome sequencing analyses have revealed the presence of an APOBEC mutation signature in multiple cancer types, including breast, bladder, thyroid, and cervix cancer, B cell lymphoma, lung adenocarcinoma (LUAD), acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), and multiple myelomas (MM).…”

“…Each member of this family shares at least one zinc-dependent deaminase (ZDD) containing the consensus amino acid sequence H-X-E-X23-28-P-C-X2-4-C, where X represents any amino acid. While the histidine (H) and cysteine (C) residues bind zinc at the active site, the glutamic acid residue (E) regulates proton shuttling through deamination [ 37 , 38 , 39 ]. APOBECs catalyze cytosine deamination into uracil through a zinc-mediated hydrolytic mechanism.…”

“…Of note, A3B expression and catalytic activity were associated with increased genomic uracil levels, dC > dT transition rates and mutation frequencies [ 51 ]. Finally, APOBEC3 proteins have been proposed to link viral infections to cancer development [ 39 ], an interesting aspect that will be further addressed in the following section.…”

“…ZDD: Zinc-dependent deaminase. (Modified from [ 39 ]) ( B ) Reaction of the ssDNA cytosine deamination catalyzed by APOBEC family members.…”

HPV‐16/18 E6‐induced APOBEC3B expression associates with proliferation of cervical cancer cells and hypomethylation of Cyclin D1

“…The p53 and retinoblastoma (RB) proteins are well‐characterized host targets of viral E6 and E7, 12,13 leading to increased genomic instability, accumulation of somatic mutations, and in some cases integration of HPV into the host genome 14 . In 2017, The Cancer Genome Atlas (TCGA) project shed light on novel methods to identify clinical and molecular associations as well as functionally altered signaling pathways that may drive tumorigenesis, suggesting that apolipoprotein B messenger RNA (mRNA) editing enzyme, catalytic polypeptide ( APOBEC ) mutagenesis is the predominant source of mutations in cervical cancers 15,16 . However, the mechanisms by which differences develop between CIN and cervical cancer after HPV infection remain poorly understood.…”