Defective expression of ATG4D abrogates autophagy and promotes growth in human uterine fibroids

Abstract

Uterine fibroids (UF) are the most common pelvic tumors in women of reproductive-age and they usually cause heavy menstrual bleeding, pain and infertility. Autophagy is a collection of processes that enables the cells to digest and recycle their cytoplasmic contents, such as toxic protein aggregates, defunct or disused organelles and invading microorganisms. Dysregulation in autophagy process were described in neoplasms; however, the contribution of autophagy to the pathogenesis of UF remains unknown. In this study, we demonstrate that autophagy is deregulated in human UF as evidenced by significant accumulation of autophagosome in human UF cells compared to normal myometrium cells. Analysis of the autophagy markers revealed an enhanced initiation of the autophagy in UF tissues compared to their adjacent myometrial tissues (MyoF). However, autophagosome maturation and flux was blocked in UF tissues, as marked by accumulation of LC3-B and P62 protein. This block was associated with defective expression of autophagy-related protein 4 (ATG4) in the UF tissues compared to MyoF in ~90% of patient samples. Silencing of ATG4D in normal human myometrial cells resulted in defective autophagy flux, enhanced cell proliferation and increased extracellular matrix production, which phenocopy UF cell line. This study indicates that impairment of autophagy flux secondary to defective expression of ATG4D expression is a new mechanistic aberration that contributes to UF pathogenesis. Targeting autophagy pathway could provide novel medical therapeutic approach for non-surgical treatment of UF.

Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux

“…*p < 0.05, **p < 0.01, ***p < 0.001, NS: not significant proliferation of primarily cultured glioblastoma cells from patients (Additional file 3: Figure S3). A large body of evidence suggests that inhibition of the activity of other ATG4 family members, including ATG4A, ATG4B and ATG4D, could suppress tumor progression and enhance chemosensitivity or the efficacy of radiotherapy [42][43][44][45][46][47][48][49]. These findings consistently implied that the ATG4 family played an important role in tumorigenesis and cancer therapy.…”

Identification and Validation of an Individualized Autophagy-Clinical Prognostic Index in Gastric Cancer Patients

“…Research by Ngollo et al Showed that GRID2 interacts with H3K27me3 in prostate cancer and is signi cantly overexpressed. [30] The protein encoded by ATG4D belongs to the ATG4 mammalian family (four cysteine proteases, ATG4A4D class), which is closely related to autophagosome maturation and apoptosis pathways [31]. Gil et al's research shows that ATG4D can play a role as a tumor suppressor in the development of colorectal cancer [32].…”

“…Gil et al's research shows that ATG4D can play a role as a tumor suppressor in the development of colorectal cancer [32]. Similarly, ATG4D's defective expression will eliminate autophagy and promote the growth of human uterine broids [33]. The members of the GABARAP (gamma-aminobutyric acid hand-related protein) family (GABARAP, GABARAPL1 / GEC1 and GABARAPL2 / GATE-16) are one of the subfamilies of the ATG8 family of proteins, and are closely related to the intracellular transport of receptors and the autophagy pathway [34].…”

The flavonoids of Sophora flavescens exerts anti-inflammatory activity via promoting autophagy of Bacillus Calmette-Guérin-stimulated macrophages

“…Based on the screening results of qPCR array for gene profiling of autophagy pathway-related genes (data not shown), we investigated the gene expression across 8 different key regulators of autophagy flux-related genes including Cathepsin S (CTSS), AMBRA1, EIF4G1, ATG3, ATG4D, ATG9A, RAB24, and FBXL20, using RT-qPCR. [35][36][37][38][39] The RT-qPCR results showing gene expression in MH-S cells (Fig. 8A) and mouse peritoneal macrophages ( 40,41 which are a group of natural compounds with variable phenolic structures and ubiquitously present in plants.…”