PMID- 34408002 OWN - NLM STAT- MEDLINE DCOM- 20220111 LR - 20220111 IS - 1538-7445 (Electronic) IS - 0008-5472 (Linking) VI - 81 IP - 21 DP - 2021 Nov 1 TI - PDSS1-Mediated Activation of CAMK2A-STAT3 Signaling Promotes Metastasis in Triple-Negative Breast Cancer. PG - 5491-5505 LID - 10.1158/0008-5472.CAN-21-0747 [doi] AB - Genomic alterations are crucial for the development and progression of human cancers. Copy-number gains found in genes encoding metabolic enzymes may induce triple-negative breast cancer (TNBC) adaptation. However, little is known about how metabolic enzymes regulate TNBC metastasis. Using our previously constructed multiomic profiling of a TNBC cohort, we identified decaprenyl diphosphate synthase subunit 1 (PDSS1) as an essential gene for TNBC metastasis. PDSS1 expression was significantly upregulated in TNBC tissues compared with adjacent normal tissues and was positively associated with poor survival among patients with TNBC. PDSS1 knockdown inhibited TNBC cell migration, invasion, and distant metastasis. Mechanistically, PDSS1, but not a catalytically inactive mutant, positively regulated the cellular level of coenzyme Q10 (CoQ10) and intracellular calcium levels, thereby inducing CAMK2A phosphorylation, which is essential for STAT3 phosphorylation in the cytoplasm. Phosphorylated STAT3 entered the nucleus, promoting oncogenic STAT3 signaling and TNBC metastasis. STAT3 phosphorylation inhibitors (e.g., Stattic) effectively blocked PDSS1-induced cell migration and invasion in vitro and tumor metastasis in vivo. Taken together, our study highlights the importance of targeting the previously uncharacterized PDSS1/CAMK2A/STAT3 oncogenic signaling axis, expanding the repertoire of precision medicine in TNBC. SIGNIFICANCE: A novel metabolic gene PDSS1 is highly expressed in triple-negative breast cancer tissues and contributes to metastasis, serving as a potential therapeutic target for combating metastatic disease. CI - (c)2021 American Association for Cancer Research. FAU - Yu, Tian-Jian AU - Yu TJ AD - Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. AD - Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R. China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China. FAU - Liu, Ying-Ying AU - Liu YY AD - Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. AD - Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R. China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China. FAU - Li, Xiao-Guang AU - Li XG AD - Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. AD - Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R. China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China. AD - Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. FAU - Lian, Bi AU - Lian B AD - Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. AD - Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R. China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China. FAU - Lu, Xun-Xi AU - Lu XX AUID- ORCID: 0000-0002-5118-0377 AD - Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. AD - Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R. China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China. FAU - Jin, Xi AU - Jin X AD - Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. AD - Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R. China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China. FAU - Shao, Zhi-Ming AU - Shao ZM AUID- ORCID: 0000-0001-8781-2455 AD - Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. AD - Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R. China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China. AD - Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. FAU - Hu, Xin AU - Hu X AD - Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. yizhoujiang@fudan.edu.cn genhongdi@163.com xinhu@fudan.edu.cn. AD - Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R. China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China. AD - Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. FAU - Di, Gen-Hong AU - Di GH AD - Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. yizhoujiang@fudan.edu.cn genhongdi@163.com xinhu@fudan.edu.cn. AD - Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R. China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China. AD - Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. FAU - Jiang, Yi-Zhou AU - Jiang YZ AD - Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. yizhoujiang@fudan.edu.cn genhongdi@163.com xinhu@fudan.edu.cn. AD - Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, P.R. China. AD - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, P.R. China. AD - Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, P.R. China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210818 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (Biomarkers, Tumor) RN - 0 (STAT3 Transcription Factor) RN - 0 (STAT3 protein, human) RN - EC 2.5.- (Alkyl and Aryl Transferases) RN - EC 2.5.1.- (prenyldiphosphate synthase, subunit 1, human) RN - EC 2.7.11.17 (CAMK2A protein, human) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) SB - IM MH - Alkyl and Aryl Transferases/genetics/*metabolism MH - Animals MH - Apoptosis MH - Biomarkers, Tumor/genetics/*metabolism MH - Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics/*metabolism MH - Cell Movement MH - Cell Proliferation MH - Female MH - *Gene Expression Regulation, Neoplastic MH - Humans MH - Lung Neoplasms/genetics/metabolism/*secondary MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Neoplasm Invasiveness MH - Prognosis MH - STAT3 Transcription Factor/genetics/*metabolism MH - Survival Rate MH - Triple Negative Breast Neoplasms/genetics/metabolism/*pathology MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays EDAT- 2021/08/20 06:00 MHDA- 2022/01/12 06:00 CRDT- 2021/08/19 05:55 PHST- 2021/03/07 00:00 [received] PHST- 2021/07/04 00:00 [revised] PHST- 2021/08/16 00:00 [accepted] PHST- 2021/08/20 06:00 [pubmed] PHST- 2022/01/12 06:00 [medline] PHST- 2021/08/19 05:55 [entrez] AID - 0008-5472.CAN-21-0747 [pii] AID - 10.1158/0008-5472.CAN-21-0747 [doi] PST - ppublish SO - Cancer Res. 2021 Nov 1;81(21):5491-5505. doi: 10.1158/0008-5472.CAN-21-0747. Epub 2021 Aug 18.