Identification of COQ2 as a regulator of proliferation and lipid peroxidation through genome-scale CRISPR-Cas9 screening in myeloma cells
© 2024 British Society for Haematology and John Wiley & Sons Ltd..
Multiple myeloma (MM) is the second most common malignant haematological disease with a poor prognosis. The limit therapeutic progress has been made in MM patients with cancer relapse, necessitating deeper research into the molecular mechanisms underlying its occurrence and development. A genome-wide CRISPR-Cas9 loss-of-function screening was utilized to identify potential therapeutic targets in our research. We revealed that COQ2 plays a crucial role in regulating MM cell proliferation and lipid peroxidation (LPO). Knockout of COQ2 inhibited cell proliferation, induced cell cycle arrest and reduced tumour growth in vivo. Mechanistically, COQ2 promoted the activation of the MEK/ERK cascade, which in turn stabilized and activated MYC protein. Moreover, we found that COQ2-deficient MM cells increased sensitivity to the LPO activator, RSL3. Using an inhibitor targeting COQ2 by 4-CBA enhanced the sensitivity to RSL3 in primary CD138+ myeloma cells and in a xenograft mouse model. Nevertheless, co-treatment of 4-CBA and RSL3 induced cell death in bortezomib-resistant MM cells. Together, our findings suggest that COQ2 promotes cell proliferation and tumour growth through the activation of the MEK/ERK/MYC axis and targeting COQ2 could enhance the sensitivity to ferroptosis in MM cells, which may be a promising therapeutic strategy for the treatment of MM patients.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:204 |
|---|---|
| Enthalten in: |
British journal of haematology - 204(2024), 4 vom: 11. Apr., Seite 1307-1324 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Li, Miao [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
4-hydroxybenzoate polyprenyltransferase |
|---|
| Anmerkungen: |
Date Completed 11.04.2024 Date Revised 16.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1111/bjh.19375 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369525035 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369525035 | ||
| 003 | DE-627 | ||
| 005 | 20240417232618.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240311s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1111/bjh.19375 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1378.xml |
| 035 | |a (DE-627)NLM369525035 | ||
| 035 | |a (NLM)38462771 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Li, Miao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identification of COQ2 as a regulator of proliferation and lipid peroxidation through genome-scale CRISPR-Cas9 screening in myeloma cells |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 11.04.2024 | ||
| 500 | |a Date Revised 16.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024 British Society for Haematology and John Wiley & Sons Ltd. | ||
| 520 | |a Multiple myeloma (MM) is the second most common malignant haematological disease with a poor prognosis. The limit therapeutic progress has been made in MM patients with cancer relapse, necessitating deeper research into the molecular mechanisms underlying its occurrence and development. A genome-wide CRISPR-Cas9 loss-of-function screening was utilized to identify potential therapeutic targets in our research. We revealed that COQ2 plays a crucial role in regulating MM cell proliferation and lipid peroxidation (LPO). Knockout of COQ2 inhibited cell proliferation, induced cell cycle arrest and reduced tumour growth in vivo. Mechanistically, COQ2 promoted the activation of the MEK/ERK cascade, which in turn stabilized and activated MYC protein. Moreover, we found that COQ2-deficient MM cells increased sensitivity to the LPO activator, RSL3. Using an inhibitor targeting COQ2 by 4-CBA enhanced the sensitivity to RSL3 in primary CD138+ myeloma cells and in a xenograft mouse model. Nevertheless, co-treatment of 4-CBA and RSL3 induced cell death in bortezomib-resistant MM cells. Together, our findings suggest that COQ2 promotes cell proliferation and tumour growth through the activation of the MEK/ERK/MYC axis and targeting COQ2 could enhance the sensitivity to ferroptosis in MM cells, which may be a promising therapeutic strategy for the treatment of MM patients | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a MYC | |
| 650 | 4 | |a bortezomid resistant | |
| 650 | 4 | |a lipid peroxidation | |
| 650 | 4 | |a multiple myeloma | |
| 650 | 7 | |a Mitogen-Activated Protein Kinase Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.12.2 |2 NLM | |
| 650 | 7 | |a 4-hydroxybenzoate polyprenyltransferase |2 NLM | |
| 650 | 7 | |a EC 2.5.1.- |2 NLM | |
| 700 | 1 | |a Zhang, Chang-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Di-Sheng |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Sze-Hoi |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xue-Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Shu-Na |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Zi-Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Ju, Fei-Er |e verfasserin |4 aut | |
| 700 | 1 | |a Sang, Xiao-Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zi-Xuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qiao-Xia |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Yu-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Si-Si |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiao-Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xing-Ding |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Xin |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t British journal of haematology |d 1955 |g 204(2024), 4 vom: 11. Apr., Seite 1307-1324 |w (DE-627)NLM000000396 |x 1365-2141 |7 nnns |
| 773 | 1 | 8 | |g volume:204 |g year:2024 |g number:4 |g day:11 |g month:04 |g pages:1307-1324 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1111/bjh.19375 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 204 |j 2024 |e 4 |b 11 |c 04 |h 1307-1324 | ||