GOLPH3L, a paralog of GOLPH3, is a phosphatidylinositol-4-phosphate-binding membrane protein. It plays essential roles in maintaining Golgi localization of LYSET and a functional mannose 6-phosphate transport pathway, ensuring the integrity of the M6P-tagging machinery and lysosomal homeostasis [3]. It also acts as a broad-spectrum COPI adaptor for sorting into intra-Golgi transport vesicles, impinging on most glycosylation pathways of the Golgi [4]. Additionally, it is involved in determining Golgi morphology, with its expression perturbations having opposite effects on Golgi morphology compared to GOLPH3 [6].

Genetic GOLPH3L ablation in radiotherapy-resistant glioblastoma cells augmented antitumor immunity and overcame tumor resistance to radiotherapy. GOLPH3L interacted with STING after radiotherapy, suppressing STING-NLRP3-mediated pyroptosis and resulting in an immunosuppressive tumor immune microenvironment [1]. In epithelial ovarian cancer, high GOLPH3L expression was associated with poor prognosis, and knockdown of GOLPH3L in cell lines reduced cell viability [2]. In breast cancer, knockdown of GOLPH3L suppressed cell proliferation, survival, and migration, while overexpression promoted aggressive tumorigenic activities. GOLPH3L was found to promote central carbon metabolism in breast cancer by stabilizing SERPINE1 [5]. In cervical cancer, GOLPH3L overexpression was associated with advanced FIGO staging, stromal invasion, lymph node metastasis, and poor response to neoadjuvant chemotherapy. Knockdown of GOLPH3L induced cell cycle arrest, increased apoptosis, and cisplatin sensitivity [7]. In rhabdomyosarcoma, knockdown of GOLPH3L prevented the proliferation of cell lines [8]. In ovarian carcinoma, GOLPH3L overexpression was associated with cisplatin resistance, and inhibition of GOLPH3L sensitized cells to CDDP cytotoxicity. GOLPH3L activated the NF-κB signaling pathway [9].

In conclusion, GOLPH3L is crucial for Golgi-related functions such as glycosylation and maintaining organelle morphology. Through gene-knockout or knockdown models in various cancer types like glioblastoma, ovarian, breast, cervical cancer, and rhabdomyosarcoma, it has been revealed that GOLPH3L plays significant roles in tumor-related processes including immune microenvironment regulation, cell proliferation, survival, metastasis, and drug resistance. These findings suggest that targeting GOLPH3L could be a potential strategy for cancer treatment.

References:

1. Sun, Shuo, Qian, Shiyu, Wang, Ran, Chen, Yun, Liu, Hongyi. 2025. Targeting GOLPH3L improves glioblastoma radiotherapy by regulating STING-NLRP3-mediated tumor immune microenvironment reprogramming. In Science translational medicine, 17, eado0020. doi:10.1126/scitranslmed.ado0020. https://pubmed.ncbi.nlm.nih.gov/40043140/

2. Feng, Yanling, He, Fan, Wu, Huini, Han, Xian, Liu, Jihong. 2015. GOLPH3L is a Novel Prognostic Biomarker for Epithelial Ovarian Cancer. In Journal of Cancer, 6, 893-900. doi:10.7150/jca.11865. https://pubmed.ncbi.nlm.nih.gov/26284141/

3. Brauer, Berit K, Chen, Zilei, Beirow, Felix, Jabs, Sabrina, Voss, Matthias. 2024. GOLPH3 and GOLPH3L maintain Golgi localization of LYSET and a functional mannose 6-phosphate transport pathway. In The EMBO journal, 43, 6264-6290. doi:10.1038/s44318-024-00305-z. https://pubmed.ncbi.nlm.nih.gov/39587297/

4. Welch, Lawrence G, Peak-Chew, Sew-Yeu, Begum, Farida, Stevens, Tim J, Munro, Sean. 2021. GOLPH3 and GOLPH3L are broad-spectrum COPI adaptors for sorting into intra-Golgi transport vesicles. In The Journal of cell biology, 220, . doi:10.1083/jcb.202106115. https://pubmed.ncbi.nlm.nih.gov/34473204/

5. Xu, Youqin, Chen, Wancheng, Liang, Jing, Chen, Wenxiao, Huang, Wenhua. 2021. The miR-1185-2-3p-GOLPH3L pathway promotes glucose metabolism in breast cancer by stabilizing p53-induced SERPINE1. In Journal of experimental & clinical cancer research : CR, 40, 47. doi:10.1186/s13046-020-01767-9. https://pubmed.ncbi.nlm.nih.gov/33509226/

6. Ng, Michelle M, Dippold, Holly C, Buschman, Matthew D, Noakes, Christopher J, Field, Seth J. 2013. GOLPH3L antagonizes GOLPH3 to determine Golgi morphology. In Molecular biology of the cell, 24, 796-808. doi:10.1091/mbc.E12-07-0525. https://pubmed.ncbi.nlm.nih.gov/23345592/

7. Feng, Yanling, He, Fan, Yan, Shumei, Gao, Bei, Liu, Jihong. 2017. The Role of GOLPH3L in the Prognosis and NACT response in Cervical Cancer. In Journal of Cancer, 8, 443-454. doi:10.7150/jca.17096. https://pubmed.ncbi.nlm.nih.gov/28261346/

8. Kunigou, Osamu, Nagao, Hiroko, Kawabata, Naoya, Komiya, Setsuro, Setoguchi, Takao. 2011. Role of GOLPH3 and GOLPH3L in the proliferation of human rhabdomyosarcoma. In Oncology reports, 26, 1337-42. doi:10.3892/or.2011.1413. https://pubmed.ncbi.nlm.nih.gov/21822541/

9. He, Shanyang, Niu, Gang, Shang, Jianhong, You, Zeshan, Shen, Hongwei. 2017. The oncogenic Golgi phosphoprotein 3 like overexpression is associated with cisplatin resistance in ovarian carcinoma and activating the NF-κB signaling pathway. In Journal of experimental & clinical cancer research : CR, 36, 137. doi:10.1186/s13046-017-0607-0. https://pubmed.ncbi.nlm.nih.gov/28978336/