Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.
Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, California.
Mol Cancer Res. 2024 Apr 2;22(4):386-401. doi: 10.1158/1541-7786.MCR-23-0445.
Calcium homeostasis is critical for cell proliferation, and emerging evidence shows that cancer cells exhibit altered calcium signals to fulfill their need for proliferation. However, it remains unclear whether there are oncogene-specific calcium homeostasis regulations that can expose novel therapeutic targets. Here, from RNAi screen, we report that adenosylhomocysteinase like protein 1 (AHCYL1), a suppressor of the endoplasmic reticulum (ER) calcium channel protein inositol trisphosphate receptor (IP3R), is selectively upregulated and critical for cell proliferation and tumor growth potential of human NRAS-mutated melanoma, but not for melanoma expressing BRAF V600E. Mechanistically, AHCYL1 deficiency results in decreased ER calcium levels, activates the unfolded protein response (UPR), and triggers downstream apoptosis. In addition, we show that AHCYL1 transcription is regulated by activating transcription factor 2 (ATF2) in NRAS-mutated melanoma. Our work provides evidence for oncogene-specific calcium regulations and suggests AHCYL1 as a novel therapeutic target for RAS mutant-expressing human cancers, including melanoma.
Our findings suggest that targeting the AHCYL1-IP3R axis presents a novel therapeutic approach for NRAS-mutated melanomas, with potential applicability to all cancers harboring RAS mutations, such as KRAS-mutated human colorectal cancers.
钙稳态对于细胞增殖至关重要，新出现的证据表明，癌细胞表现出改变的钙信号以满足其增殖的需求。然而，目前尚不清楚是否存在癌基因特异性的钙稳态调节，可以揭示新的治疗靶点。在这里，我们通过 RNAi 筛选报告，腺苷同型半胱氨酸酶样蛋白 1（AHCYL1）是内质网（ER）钙通道蛋白三磷酸肌醇受体（IP3R）的抑制剂，它选择性地上调并且对人NRAS 突变黑色素瘤的细胞增殖和肿瘤生长潜力至关重要，但对表达 BRAF V600E 的黑色素瘤则不然。从机制上讲，AHCYL1 缺乏会导致 ER 钙水平降低，激活未折叠蛋白反应（UPR），并引发下游细胞凋亡。此外，我们表明 AHCYL1 转录受 NRAS 突变黑色素瘤中激活转录因子 2（ATF2）的调节。我们的工作为癌基因特异性钙调节提供了证据，并表明 AHCYL1 是一种新型的治疗靶点，可用于表达 RAS 突变的人类癌症，包括黑色素瘤。
我们的发现表明，靶向 AHCYL1-IP3R 轴为 NRAS 突变黑色素瘤提供了一种新的治疗方法，对于所有携带 RAS 突变的癌症，如 KRAS 突变的人结直肠癌，都具有潜在的适用性。
