GALNT7 promotes hepatocellular carcinoma progression by activating the PI3K/AKT signaling pathway via O-glycosylation of MUC13

Abstract

Hepatocellular carcinoma (HCC) represents a significant global health challenge due to its aggressive malignancy. Abnormal glycosylation is a frequent phenomenon in tumor cells and manifests as alterations in key cancer biomarkers. This phenomenon is driven primarily by changes in the expressions of glycosyltransferases. Our study focuses on GALNT7, a member of the GALNT glycosyltransferase family, which catalyzes the initiation of O-linked glycan synthesis by transferring N-acetylgalactosamine (GalNAc) to serine or threonine residues on target proteins. We observe that GALNT7 expression is notably increased in HCC tissues and is correlated with increased tumor cell invasion, migration, and proliferation, alongside with reduced apoptosis, both in vivo and in vitro. Further molecular analyses indicate that GALNT7 specifically modifies the O-glycosylation pattern of MUC13, thereby influencing the activation of the PI3K/AKT signaling pathway. Additionally, elevated GALNT7 level enhances resistance to lenvatinib-based chemotherapy regimens. Thus, GALNT7 is a critical regulator of oncogenic processes in HCC. Targeting the GALNT7-MUC13-PI3K/AKT axis represents a novel therapeutic strategy for combating HCC.

1. Introduction

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and is responsible for the third most significant number of cancer-related deaths [1,2]. Despite the efficacy of treatment modalities such as surgical resection, immunotherapy, molecular targeted therapy, and liver transplantation in increasing survival rates, the prognosis for patients with HCC remains unfavorable. This is primarily attributed to challenges in the early detection of the recurrence and metastasis of HCC cells [3]. Therefore, it is imperative to comprehensively understand the etiology of HCC to develop novel therapeutic approaches.

Protein glycosylation is a prevalent and intricate posttranslational modification of generated proteins. It is a crucial regulatory mechanism in fundamental molecular and cellular biological processes [4]. Abnormal protein glycosylations were recently recognized as indicators of cancer and are linked to the malignant conversion of different kinds of cancers [5]. Recent glycobiology research suggests that abnormal protein glycosylation in liver cells promotes the development of HCC by influencing many cancer-promoting signaling pathways. The proliferation, invasion, metastasis, immune evasion, and resistance to therapy of cancer cells are characteristic features of HCC [6]. Glycosylation is a biochemical process facilitated by glycosyltransferases, a group of enzymes consisting of at least 200 members. The dysregulation of glycosyltransferases is frequently observed in cancer, indicating their potential functions as either oncogenes or tumor suppressor genes [7,8]. Hence, elucidating the connection between glycosyltransferases and HCC is highly important.

GALNT7 is an enzyme that adds N-acetylgalactosamine (GalNAc) to the Ser/Thr side chains of proteins, initiating O-linked glycan biosynthesis, which plays a role in regulating the first stages of mucin-type O-glycosylation [9]. Abnormal GALNT7 expression is linked to several cancer types, such as prostate [10], cervical [11], breast [12], colorectal [13,14], and thyroid [15] cancers. The effects of GALNT7 on glycosylation in HCC cells and its molecular mechanisms remain largely unknown.