NRAS Mutant Dictates AHCYL1-Governed ER Calcium Homeostasis for Melanoma Tumor Growth.
Mol Cancer Res
; 22(4): 386-401, 2024 04 02.
Article
en En
| MEDLINE
| ID: mdl-38294692
ABSTRACT
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. IMPLICATIONS 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Adenosilhomocisteinasa
/
Retículo Endoplásmico
/
Melanoma
Límite:
Humans
Idioma:
En
Revista:
Mol Cancer Res
Asunto de la revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Año:
2024
Tipo del documento:
Article