PMID- 38294692 OWN - NLM STAT- MEDLINE DCOM- 20240403 LR - 20240408 IS - 1557-3125 (Electronic) IS - 1541-7786 (Print) IS - 1541-7786 (Linking) VI - 22 IP - 4 DP - 2024 Apr 2 TI - NRAS Mutant Dictates AHCYL1-Governed ER Calcium Homeostasis for Melanoma Tumor Growth. PG - 386-401 LID - 10.1158/1541-7786.MCR-23-0445 [doi] AB - 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. CI - (c)2024 American Association for Cancer Research. FAU - Cai, Chufan AU - Cai C AUID- ORCID: 0000-0001-6209-0820 AD - Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. FAU - Tu, Jiayi AU - Tu J AUID- ORCID: 0000-0002-2626-0084 AD - Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. FAU - Najarro, Jeronimo AU - Najarro J AUID- ORCID: 0009-0001-2600-7871 AD - Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. FAU - Zhang, Rukang AU - Zhang R AUID- ORCID: 0000-0001-9554-4999 AD - Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. FAU - Fan, Hao AU - Fan H AUID- ORCID: 0000-0001-5245-9698 AD - Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. FAU - Zhang, Freya Q AU - Zhang FQ AUID- ORCID: 0000-0002-2596-0433 AD - Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. FAU - Li, Jiacheng AU - Li J AUID- ORCID: 0000-0003-3730-3534 AD - Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. FAU - Xie, Zhicheng AU - Xie Z AUID- ORCID: 0009-0003-3990-0508 AD - Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. FAU - Su, Rui AU - Su R AUID- ORCID: 0000-0002-4807-6229 AD - Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, California. FAU - Dong, Lei AU - Dong L AUID- ORCID: 0000-0001-9574-0148 AD - Department of Systems Biology, Beckman Research Institute of City of Hope, Duarte, California. FAU - Arellano, Nicole AU - Arellano N AUID- ORCID: 0000-0003-1618-0467 AD - The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois. FAU - Ciboddo, Michele AU - Ciboddo M AUID- ORCID: 0000-0002-5175-5185 AD - The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois. FAU - Elf, Shannon E AU - Elf SE AUID- ORCID: 0000-0002-8845-3818 AD - The Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois. FAU - Gao, Xue AU - Gao X AUID- ORCID: 0009-0006-4127-3808 AD - Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. FAU - Chen, Jing AU - Chen J AUID- ORCID: 0000-0002-5376-9062 AD - Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. FAU - Wu, Rong AU - Wu R AUID- ORCID: 0000-0001-6091-8364 AD - Section of Hematology and Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois. LA - eng GR - P30 CA014599/CA/NCI NIH HHS/United States GR - R01 CA174786/CA/NCI NIH HHS/United States GR - R01 CA140515/CA/NCI NIH HHS/United States GR - R01 CA276568/CA/NCI NIH HHS/United States PT - Journal Article PL - United States TA - Mol Cancer Res JT - Molecular cancer research : MCR JID - 101150042 RN - EC 3.3.1.1 (Adenosylhomocysteinase) RN - SY7Q814VUP (Calcium) RN - EC 3.6.1.- (GTP Phosphohydrolases) RN - 0 (Membrane Proteins) RN - EC 3.6.1.- (NRAS protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) SB - IM MH - Humans MH - *Adenosylhomocysteinase/metabolism MH - Calcium MH - Cell Line, Tumor MH - *Endoplasmic Reticulum/metabolism MH - GTP Phosphohydrolases/genetics MH - Homeostasis MH - *Melanoma/metabolism/pathology MH - Membrane Proteins/genetics/metabolism MH - Mutation MH - Proto-Oncogene Proteins B-raf/genetics/metabolism PMC - PMC10987265 MID - NIHMS1965351 COIS- Competing interests: Authors declare that they have no competing interests. EDAT- 2024/01/31 12:42 MHDA- 2024/04/03 06:44 PMCR- 2024/10/02 CRDT- 2024/01/31 11:19 PHST- 2023/06/03 00:00 [received] PHST- 2023/10/27 00:00 [revised] PHST- 2024/01/29 00:00 [accepted] PHST- 2024/10/02 00:00 [pmc-release] PHST- 2024/04/03 06:44 [medline] PHST- 2024/01/31 12:42 [pubmed] PHST- 2024/01/31 11:19 [entrez] AID - 734033 [pii] AID - 10.1158/1541-7786.MCR-23-0445 [doi] PST - ppublish SO - Mol Cancer Res. 2024 Apr 2;22(4):386-401. doi: 10.1158/1541-7786.MCR-23-0445.