GHITM regulates malignant phenotype and sensitivity to PD‐1 blockade of renal cancer cells via Notch signalling

• Published in: Journal of cellular and molecular medicine Vol. 28; no. 8; pp. e18290 - n/a
• Main Authors: Huang, Shiyu, Liu, Jiachen, Hu, Juncheng, Hou, Yanguang, Hu, Min, Zhang, Banghua, Luo, Hongbo, Fu, Shujie, Chen, Yujie, Liu, Xiuheng, Chen, Zhiyuan, Wang, Lei
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.04.2024; John Wiley and Sons Inc
• Subjects: Antibodies; Biomarkers; Cancer therapies; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Cell culture; Cell growth; Cell migration; Cell proliferation; Down-regulation; Gene expression; GHITM; Growth hormones; Humans; Immunotherapy; Kidney; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; L1 protein; malignant phenotype; Medical prognosis; Metastasis; Nomograms; Notch signalling; Notch1 protein; Original; Patients; PD-1 protein; PD-L1 protein; Phenotype; Phenotypes; Plasmids; Programmed Cell Death 1 Receptor; Proteins; renal cancer; Renal cell carcinoma; Signal transduction; Therapeutic targets; Tumorigenesis; United States > US; China; malignant phenotype; renal cancer; GHITM; Notch signalling; immunotherapy
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.18290

Growth hormone inducible transmembrane protein (GHITM), one member of Bax inhibitory protein‐like family, has been rarely studied, and the clinical importance and biological functions of GHITM in kidney renal clear cell carcinoma (KIRC) still remain unknown. In the present study, we found that GHITM was downregulated in KIRC. Aberrant GHITM downregulation related to clinicopathological feature and unfavourable prognosis of KIRC patients. GHITM overexpression inhibited KIRC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, GHITM overexpression could induce the downregulation of Notch1, which acts as an oncogene in KIRC. Overexpression of Notch1 effectively rescued the inhibitory effect induced by GHITM upregulation. More importantly, GHITM could regulate PD‐L1 protein abundance and ectopic overexpression of GHITM enhanced the antitumour efficiency of PD‐1 blockade in KIRC, which provided new insights into antitumour therapy. Furthermore, we also showed that YY1 could decrease GHITM level via binding to its promoter. Taken together, our study revealed that GHITM was a promising therapeutic target for KIRC, which could modulate malignant phenotype and sensitivity to PD‐1 blockade of renal cancer cells via Notch signalling pathway.