The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization

Abstract

Mitophagy is a vital process that controls mitochondria quality, dysregulation of which can promote cancer. Oncoprotein mucin 1 (MUC1) targets mitochondria to attenuate drug-induced apoptosis. However, little is known about whether and how MUC1 contributes to mitochondrial homeostasis in cancer cells. We identified a novel role of MUC1 in promoting mitophagy. Increased mitophagy is coupled with the translocation of MUC1 to mitochondria, where MUC1 interacts with and induces degradation of ATPase family AAA domain-containing 3A (ATAD3A), resulting in protection of PTEN-induced kinase 1 (Pink1) from ATAD3A-mediated cleavage. Interestingly, MUC1-induced mitophagy is associated with increased oncogenicity of cancer cells. Similarly, inhibition of mitophagy significantly suppresses MUC1-induced cancer cell activity in vitro and in vivo. Consistently, MUC1 and ATAD3A protein levels present an inverse relationship in tumor tissues of breast cancer patients. Our data validate that MUC1/ATAD3A/Pink1 axis-mediated mitophagy constitutes a novel mechanism for maintaining the malignancy of cancer cells, providing a novel therapeutic approach for MUC1-positive cancers.

Identification of ATAD3A as a key regulator in non‐small cell lung cancer by promoting STAT3‐induced cell proliferation and tumor angiogenesis

“…ATAD3A knockdown promotes the growth of hepatocellular carcinoma xenograft tumors 18 . In breast cancer, ATAD3A was also found to act as a tumor suppressor gene, and overexpression of ATAD3A inhibited cancer cell proliferation and tumorigenesis 11 . However, other studies have reported that ATAD3A plays a pro‐oncogenic role in the development of tumors such as prostate cancer and head and neck cancer 8,19 .…”

“…This promotes proliferation and invasion of head and neck cancer cells 8 . ATAD3A not only plays an important role in the epithelial–mesenchymal transition of tumor cells, but also affects other biological processes, such as DNA repair and cell apoptosis in tumor cells, 9,10 ultimately influencing tumor cell growth and metastasis 11 . Furthermore, ATAD3A is also involved in the sensitivity and resistance of tumor drugs.…”

Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer

“…In summary, mitochondria and breast cancer cells maintain a symbiotic relationship via multiple mechanisms that are intricately interconnected to each other to further promote breast cancer survival and growth ( Figure 2 ). Additional mitochondria-associated factors not discussed in this review, such as mitophagy and ROS-induced senescence [ 222 , 223 ], may also support breast cancer progression. Thus, targeting mitochondria is reasonable in breast cancers, and numerous drugs have been developed [ 224 , 225 ].…”

Association of mitochondrial homeostasis and dynamic balance with malignant biological behaviors of gastrointestinal cancer

“…Among prognosis study, a pan-cancer analysis demonstrated that low expressed MFN2 due to mitochondrial dysfunction was associated with poor prognosis of renal clear cell carcinoma [ 51 ]. In 321 breast cancer cases, patients with high expression of Pink1 had shorter overall survival [ 52 ]. Relevant mechanisms have been preliminarily explored.…”