Knockdown of ATG4A inhibits breast cancer progression and promotes tamoxifen chemosensitivity by suppressing autophagy

Abstract

autophagy-related 4a (aTG4a) is an autophagy regulator. The current study investigated the role of aTG4a in the development of tamoxifen-resistant breast cancer. aTG4a expression was assessed in tumor and adjacent normal tissue obtained from The cancer Genome atlas database. analyses of the disease-free survival between the aTG4a high and low expression groups was then evaluated in patients with breast cancer. cell viability and apoptosis in McF7/r cells was detected using cell counting Kit-8 assay and flow cytometry, respectively. Gene set enrichment analysis identified the pathway responsible for the effects of aTG4a. The protein expression of aTG4a, lc3, p62, Bcl-2, Bax, GSK-3β, phosphorylated (p)-GSK-3β, β-catenin, cyclind1 and c-myc in McF and McF7/r cells was determined using western blot. in this study, aTG4a expression was increased in the tumor tissues, and a higher aTG4a expression exhibited poor disease-free survival. While 4-hydroxytamoxifen (4-oHT) increased aTG4a expression in McF7 and McF7/r cells, aTG4a expression decreased in the cells treated with 3-methyladenine (3Ma). Treatment with 4-oHT and rapamycin (an autophagy activator) increased the lc3-ii/lc3-i ratio, lc3 puncta number and decreased the level of p62 in McF7/r cells. However, the effects of 4-oHT and rapamycin were reversed by 3Ma and knockdown of aTG4a, respectively. after treatment with 4-oHT, knockdown of aTG4a suppressed proliferation, triggered apoptosis, decreased the expression of Bcl-2, β-catenin, cyclin d1 and c-myc, and increased the expression of Bax and p-GSK3β in McF7/r cells. Moreover, SKl2001, an activator of the Wnt/β-catenin signaling pathway, reversed the effects of aTG4a knockdown on cell viability and apoptosis in McF7/r cells. in conclusion, the knockdown of aTG4a inhibited the anticancer effects of 4-oHT in breast cancer.

Dormancy in Breast Cancer, the Role of Autophagy, lncRNAs, miRNAs and Exosomes

“…The knockdown of ATG4A levels following 4-hydroxytamoxifen treatment led to increased cell death by apoptosis. Collectively, this study revealed that the knockdown of ATG4A leads to autophagy suppression, and increased the sensitivity of BC cells to 4-hydroxytamoxifen [104]. In our opinion, autophagy genes including BECN1, ULK1 and ATGs influence BC tumourigenic processes, hence could be strategically modulated in a context-dependent manner.…”

A degradome-based prognostic signature that correlates with immune infiltration and tumor mutation burden in breast cancer

“…The aberrant expression of a single DRG has been reported to associate with the therapeutic effects of chemotherapy ( 17 , 53 ), endocrinotherapy ( 54 ) and radiotherapy ( 55 , 56 ). In this study, the prognosis of patients undergoing endocrinotherapy or radiotherapy was worse in the high-risk group than in the low-risk group, possibly owing to treatment resistance induced by degradome dysfunction.…”

Advances in the study of autophagy in breast cancer

“…The studies outlined above demonstrate that in breast cancer, autophagy is not only influenced by tumor-related signaling pathways but also has the capacity to affect the activation status of certain tumor signaling pathways. For example, it was found that the expression of WNT pathway-related proteins was suppressed after the knockdown of ATG4A, a key regulator of cellular autophagy processes [ 60 ]. This suggests that the activation of the WNT pathway seems to have a linkage with autophagy in breast cancer cells as well.…”