Deciphering the tumor-suppressive role of PSMB9 in melanoma through multi-omics and single-cell transcriptome analyses

作者全名："Hu, Xing; Hu, Zhengang; Zhang, Hao; Zhang, Nan; Feng, Hao; Jia, Xiaomin; Zhang, Chi; Cheng, Quan"

作者地址："[Hu, Xing; Feng, Hao] Hunan Normal Univ, Affiliated Hosp 1, Hunan Prov Peoples Hosp, Dept Dermatol, Changsha 410000, Hunan, Peoples R China; [Hu, Zhengang; Zhang, Hao; Zhang, Chi; Cheng, Quan] Cent South Univ, Xiangya Hosp, Dept Neurosurg, Changsha 410008, Hunan, Peoples R China; [Zhang, Hao; Zhang, Nan] Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, Chongqing 400016, Peoples R China; [Zhang, Nan] Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Wuhan 430074, Hubei, Peoples R China; [Jia, Xiaomin] Lhasa Peoples Hosp, Dept Pathol, Lhasa 850001, Peoples R China; [Zhang, Chi; Cheng, Quan] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha 410008, Peoples R China"

通信作者："Zhang, C; Cheng, Q (通讯作者)，Cent South Univ, Xiangya Hosp, Dept Neurosurg, Changsha 410008, Hunan, Peoples R China."

来源：CANCER LETTERS

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001127954200001

JCR分区：Q1

影响因子：9.7

年份：2024

卷号：581

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Melanoma; PSMB9; Multi-omics; IFN-g; Immunotherapy

摘要："Skin cutaneous melanoma (SKCM) poses a significant challenge in skin cancers. Recent immunotherapy break-throughs have revolutionized melanoma treamtment, yet tumor heterogeneity persists as an obstacle. Epigenetic modifications orchestrated by DNA methylation contributed to tumorigenesis, thus potentially unveiling mela-noma prognosis. Here, we identified an interferon-gamma (IFN-g) sensitive subtype, which possesses favorable outcomes, robust infiltration CD8+T cells, and IFN-g score in bulk RNA-seq profile. Subsequently, we established an IFN-g sensitivity signature based on machine learning.We validated that PSMB9 is strongly correlated with immunotherapy response in both methylation and expression cohorts in this 10-probe signature. We assumed that PSMB9 acts as a putative melanoma suppressor, for its activation of CD8+T cell; capacity to modulate IFN-gamma secretion; and dynamics altering IFN-g receptors in bulk tissue. We performed single-cell RNA-seq on immunotherapy patients' tissue to uncover the nuanced role of PSMB9 in activating CD8T + cells, enhancing IFN-g, and influencing malignant cells receptors and transcrip-tional factors.Overexpress PSMB9 in two SKCM cell lines to mimic the hypomethylated state to approve our conjecture. Strong cell proliferation and migration inhibition were detected on both cells, indicating that PSMB9 is present in tumor cells and that high expression is detrimental to tumor growth and migration.Overall, comprehensive integrated analysis shows that PSMB9 emerges as a vital prognostic marker, acting predictive potential regarding immunotherapy in melanoma. This evidence not only reveals the multifaceted impact of PSMB9 on both malignant and immune cells but also serves as a prospective target for undergoing immunotherapeutic strategies in the future."

基金机构："Natural Science Foundation of Hunan Province [2023JJ30344, 2021JJ30399]; Natural Science Foundation of China [82202440]; Hunan Provincial Health Com-mission Foundation [202104122479]; Lhasa Health Technology Pro-gram Foundation [LSKJ202104]"

基金资助正文："<BOLD>Funding</BOLD> This study was supported by the Natural Science Foundation of Hunan Province (NO.2023JJ30344 and 2021JJ30399) , Natural Science Foundation of China (No. 82202440) , Hunan Provincial Health Com-mission Foundation (202104122479) , Lhasa Health Technology Pro-gram Foundation (LSKJ202104) ."