DPP3 promotes breast cancer tumorigenesis by stabilizing FASN and promoting lipid synthesis

Abstract

DPP3, a dipeptidyl peptidase, participates in a variety of pathophysiological processes. DPP3 is upregulated in cancer and might serve as a key factor in the tumorigenesis and progression of various malignancies. However, its specific role and molecular mechanism are still unknown. In this study, the expression of DPP3 in breast cancer tissues is analyzed using TCGA database. Kaplan-Meier survival analysis is performed to estimate the effect of DPP3 on the survival outcomes. To explore the biological function and mechanisms of DPP3 in breast cancer, biochemical and cell biology assays are conducted in vitro. DPP3 expresses at a higher level in breast cancer tissues than that in adjacent tissues in both TCGA database and clinical samples. Patients with high expression of DPP3 have poor survival outcomes. The proliferation and migration abilities of tumor cells with stable DPP3 knockout in breast cancer cell lines are significantly inhibited, and apoptosis is increased in vitro. GSEA analysis shows that DPP3 can affect lipid metabolism and fatty acid synthesis in tumors. Subsequent experiments show that DPP3 could stabilize FASN expression and thus promote fatty acid synthesis in tumor cells. The results of the metabolomic analysis also confirm that DPP3 can affect the content of free fatty acids. This study demonstrates that DPP3 plays a role in the reprogramming of fatty acid metabolism in tumors and is associated with poor prognosis in breast cancer patients. These findings will provide a new therapeutic target for the treatment of breast cancer.

1. Introduction

Breast cancer is the most common malignancy among women worldwide and poses a serious threat to women's health [1]. It is important to deeply explore the molecular mechanism underlying the occurrence and development of breast cancer to develop optimal treatment strategies for breast cancer patients. DPP3, a cytoplasmic peptidase (one of the protease families of EC 3.4.14), is a member of the zinc-dependent M49 metallopeptidase family. DPP3 is widely distributed in various tissues, such as red blood cells, white blood cells, lungs, heart, kidney, intestine, skeletal muscle, skin, brain, liver, and spleen, and partially in soluble form in circulating blood [2]. DPP3 can lyse a variety of bioactive peptides, including angiotensin, bilinogen enterohepatic circulation, enkephalin, endorphin and dipeptidyl derivatives, and is involved in a variety of pathophysiological processes, including blood pressure regulation, inflammation regulation and pain signaling [3,4].

In recent years, emerging studies have revealed that DPP3 is upregulated in aggressive brain glioma [5], ovarian cancer [6], endometrial cancer [7], and bowel cancer [8]. It has been shown that overexpressed DPP3 protein is associated with poor prognosis in patients with bowel cancer. In MCF-7 human breast cancer cells, the binding of DPP3 with KEAP1 stabilizes KEAP1, thereby allowing Nrf-2 to accumulate and locate in the nucleus and affect prognosis through the regulation of apoptosis [9]. The high expression of DPP3 in breast cancer indicates poor prognosis in silico; however, its specific role and molecular mechanisms are still not well known [10].

Fatty acid is one of the important energy substances in the body. Fatty acid metabolic reprogramming has recently been considered as a key driver of cancer progression and is deeply involved in the occurrence, development, metastasis and drug resistance of tumors. Several studies have shown that miRNA-328 and CDCP1 (CUB-domain containing protein 1) can promote the occurrence and metastasis of breast cancer by regulating fatty acid β-oxidation (FAO) [11,12]. Fatty acid synthesis is also essential for the distant metastasis of breast cancer and resistance to chemotherapy [13]. Li et al. [14] demonstrated that targeting the FASN/HIF1α/SLC7A11 pathway could enhance the sensitivity to sorafenib in HCC cells. Tiong et al. [15] showed that targeting the metabolic axis of SREBP-1/Hsa-Mir-497/SCAP/FASN in tumors could reverse the chemoresistant phenotype in NSCLC cells. Therefore, the reprogramming of fatty acid metabolism is an indispensable part of tumor growth, progression and treatment.