Med19 is involved in chemoresistance by mediating autophagy through HMGB1 in breast cancer

Abstract

Adriamycin (ADM)-based regimens are the most effective chemotherapeutic treatments for breast cancer. However, intrinsic and acquired chemoresistance is a major therapeutic problem. Our goal was to clarify the role of mediator complex subunit 19 (Med19) in chemotherapy resistance and to elucidate the related molecular mechanisms. In this study, ADM-resistant human cells (MCF-7/ADM) and tissues exhibited increased Med19 expression and autophagy levels relative to the corresponding control groups. Additionally, MCF-7/ADM cells showed changes in two selective markers of autophagy. There was a dose-dependent increase in the light chain 3 (LC3)-II/LC3-I ratio and a decrease in sequestosome 1 (P62/SQSTMl) expression. Furthermore, lentivirus-mediated Med19 inhibition significantly attenuated the LC3-II/LC3-I ratio, autophagy-related gene 3 (Atg3) and autophagy-related gene 5 (Atg5) expression, P62 degradation, and red fluorescent protein-LC3 dot formation after treatment with ADM or rapamycin, an autophagy activator. Furthermore, the antiproliferative effects of ADM, cisplatin (DDP), and taxol (TAX) were significantly enhanced after suppressing Med19 expression. Notably, the effects of Med19 on autophagy were mediated through the high-mobility group box-1 (HMGB1) pathway. Our findings suggest that Med19 suppression increased ADM chemosensitivity by downregulating autophagy through the inhibition of HMGB1 signaling in human breast cancer cells. Thus, the regulatory mechanisms of Med19 in autophagy should be investigated to reduce tumor resistance to chemotherapy.

The Multifaceted Functions of Autophagy in Breast Cancer Development and Treatment

“…HMGB1-mediated autophagy leads to increased chemoresistance in breast, ovarian, liver, and lung carcinomas in vitro. The subsequent depletion of HMGB1 or limiting HMGB1 cytosolic translocation diminishes autophagic protection in response to antimitotic drugs [176][177][178][179]. In line with these findings, a recent study revealed that inhibition of autophagy reduced leptin-induced cell proliferation, migration, and attenuated ERK phosphorylation [180].…”

MED19 Regulates Adipogenesis and Maintenance of White Adipose Tissue Mass by Mediating PPARγ-Dependent Gene Expression

“…However, little is known about the function of MED19. In mammals, some studies have implicated MED19 as a facilitator of RE1 silencing transcription factor (REST)-imposed neuronal gene silencing (Ding et al, 2009), as well as roles in cancer metastasis (He et al, 2016;Liu et al, 2019;Wen et al, 2013). We now identify MED19 as a key player in adipogenesis and maintenance of WAT mass.…”

High-Mobility Group Box 1 (HMGB1) Promotes Angiogenesis and Tumor Migration by Regulating Hypoxia-Inducible Factor 1 (HIF-1α) Expression via the Phosphatidylinositol 3-Kinase (PI3K)/AKT Signaling Pathway in Breast Cancer Cells

“…It is a crucial contributor to various illnesses such as sepsis, arthritis, neurodegeneration, malignancy, ischemia-reperfusion, meningitis, and aging [11–15]. The effect of HMGB1 on malignancy is complicated since it both promotes and counteracts the process of malignancy [16–18]. Suppression or enhancement of HMGB1 expression varies in different kinds of malignancies [19–21].…”