SGOL2 promotes prostate cancer progression by inhibiting RAB1A ubiquitination.

www.aging-us.com AGING 2022, Vol. 14, No. 24 Research Paper SGOL2 promotes prostate cancer progression by inhibiting RAB1A ubiquitination Tingting Lv1, Dongwei He1, Xiaokuan Zhang1, Xiaojin Guo1, Zijie Li1, Aili Zhang2, Bo Fan2, Zhiyu Wang1 1 Department of Immuno-Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei, P.R. China 2 Department of Urinary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei, P.R. China Correspondence to: Zhiyu Wang; email: Keywords: prostate cancer, SGOL2, RAB1A, ubiquitination, tumor microenvironment Received: June 9, 2022 Accepted: December 5, 2022 Published: December 23, 2022 Copyright: © 2022 Lv et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Prostate cancer is the most prevalent genitourinary malignant cancer in men worldwide. Patients with prostate cancer who progress to castration-resistant prostate cancer (CRPC) or metastatic CRPC have significantly poorer survival. Advanced prostate cancer is a clinical challenge due to the lack of effective treatment strategies. In the field of oncology, SGOL2 was an emerging and differentially expressed molecule, which enhanced the proliferation of cell populations in vitro in our studies. Mass spectrum and Co-IP validated the interaction of SGOL2 and RAB1A in a protein-protein manner. We further investigated the role of SGOL2 in the regulatory mechanism of RAB1A in prostate cancer cell lines. Furthermore, SGOL2 regulated RAB1A expression by inhibiting its ubiquitination. Rescue Experiments demonstrated that SGOL2 promoted prostate cancer cell proliferation and migration by upregulating RAB1A expression. Finally, we found that SGOL2 and RAB1A may regulate the tumor microenvironment (TME) in prostate cancer. In conclusion, our findings concluded that SGOL2 stabilized RAB1A expression to promote prostate cancer development. Both of them were of great importance in TME modulation. INTRODUCTION Prostate cancer has been newly demonstrated to have the third highest incidence of new cases among 36 cancers, behind breast cancer and lung cancer [1]. As the second most common cancer in old males around the world, therapeutic strategies remain fixed, such as radical prostatectomy and radiotherapy for localized prostate cancer and androgen deprivation treatment for advanced and metastatic forms of prostate cancer [2]. Though immunotherapy and targeted therapies have been applied in tumor treatment, the prognostic improvement for advanced prostate cancer is still slight. The pathogenesis of prostate cancer, especially progressing to metastatic castration-resistant prostate cancer (mCRPC), is a sophisticated process. Due to a www.aging-us.com 10050 boom in the field of genetics and bioinformatics, several large-scale genomic studies indicated the existence of mutations, rearrangements, gene fusion, and DNA copy number changes in primary and advanced prostate cancer [3, 4]. Therefore, there is an urgent need to link genetic abnormalities with strategies administered in personalized treatment for prostate cancer patients. Shugoshin 2 (SGO2, also known as SGOL2), which is tightly involved in the cell cycle process, has been reported to protect cohesion, sustain the linkage of chromosomes and regulate kinetochore-microtubule attachment in meiosis and mitosis [5–10]. Additionally, SGOL2 modulates the function of the subtelomere and improves HSP70 expression during heat shock to support cell survival and protein homeostasis [11, 12]. AGING A growing body of evidence indicates that SGOL2 is a novel molecule with profound significance in cancer and related fields. Up to now, what is clear is that SGOL2 has been reported as a differentially expressed gene in various types of cancer, including glioma, hepatocellular cancer, and endometrial cancer [13–15]. Previous studies had demonstrated that SGOL2 had a protein-protein interaction with BRCA1, whose variants were regarded as biomarkers to predict the survival prognosis of prostate cancer patients [16, 17]. However, the role of SGOL2 in prostate cancer development and progression remains incompletely understood. Ubiquitin is an 8.5-kDa, 76 amino acid polypeptide, which was first described in the structure of chromosomal conjugate-protein A24 as a post-translational modifier [18, 19]. The process of ubiquitination is a sequential enzymatic cascade, including three enzymatic steps: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3) [20]. Ubiquitination is a dynamically multifaceted posttranslational modification involved in many physiological activities, such as cell cycle, autography, tumorigenesis, etc. A lot of ubiquitination modifications were responsible for the development and progression of prostate cancer. Previous studies indicated that E3 ligase MDM2, STUB1, and DCAF11 were involved in androgen receptor degradation and induced androgen receptor targeted therapy resistance [21–23]. TRAF4, an E3 ubiquitin ligase, could mediate TrkA ubiquitination to active TrkA signaling pathway and thus modulate prostate cancer progression with the presence of NGF [24]. All in all, exploration of ubiquitination modifications in prostate cancer is of great significance to develop efficient therapeutic targets. In our study, SGOL2 was highly expressed in prostate cancer compared to adjacent tissue and confirmed as a pro-tumor regulator. Further exploration of the downstream mechanism elucidated that SGOL2 positively regulated RAB1A expression, a member of the GTPase family, by inhibiting its ubiquitination modification. Finally, based on our bioinformatic findings, we conjectured that SGOL2 and RAB1A both contributed to tumor microenvironment (TME) modulation in prostate cancer. RESULTS SGOL2 was overexpressed in prostate cancer and strongly associated with cancer development Considering the potential role of SGOL2 in tumorigenesis and cancer development, we first detected SGOL2 expression in prostate cancer in UALCAN [25], which revealed a significantly higher SGOL2 expression www.aging-us.com 10051 in prostate cancer tissues than in adjacent normal tissues. Moreover, SGOL2 expression tightly correlated with clinical stage and lymphatic metastasis (P<0.001) (Figure 1A–1C). We performed immunohistochemistry (IHC) to detect SGOL2 expression among 91 prostate cancer patients, which indicated that higher-grade prostate cancer expressed higher SGOL2 expression (Figure 1D). Furthermore, we evaluated the potential correlation between SGOL2 protein expression and clinicopathological characteristics and found that SGOL2 expression positively correlated with Gleason Score (r=0.213, P=0.043), pathological grade (r=0.285, P=0.007), lymphatic metastasi (...truncated)