Evidence of a synthetic lethality interaction between SETDB1 histone methyltransferase and CHD4 chromatin remodeling protein in a triple negative breast cancer cell line
During the tumorigenic process, cancer cells may become overly dependent on the activity of backup cellular pathways for their survival, representing vulnerabilities that could be exploited as therapeutic targets. Certain molecular vulnerabilities manifest as a synthetic lethality relationship, and...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Associação Brasileira de Divulgação Científica
2023-11-01
|
| Series: | Brazilian Journal of Medical and Biological Research |
| Subjects: | |
| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2023000100688&lng=en&tlng=en |
| _version_ | 1797628702811488256 |
|---|---|
| author | M.S. Moraes-Almeida M.C. Sogayar M.A.A. Demasi |
| author_facet | M.S. Moraes-Almeida M.C. Sogayar M.A.A. Demasi |
| author_sort | M.S. Moraes-Almeida |
| collection | DOAJ |
| description | During the tumorigenic process, cancer cells may become overly dependent on the activity of backup cellular pathways for their survival, representing vulnerabilities that could be exploited as therapeutic targets. Certain molecular vulnerabilities manifest as a synthetic lethality relationship, and the identification and characterization of new synthetic lethal interactions may pave the way for the development of new therapeutic approaches for human cancer. Our goal was to investigate a possible synthetic lethal interaction between a member of the Chromodomain Helicase DNA binding proteins family (CHD4) and a member of the histone methyltransferases family (SETDB1) in the molecular context of a cell line (Hs578T) representing the triple negative breast cancer (TNBC), a subtype of breast cancer lacking validated molecular targets for treatment. Therefore, we employed the CRISPR-Cas9 gene editing tool to individually or simultaneously introduce indels in the genomic loci corresponding to the catalytic domains of SETDB1 and CHD4 in the Hs578T cell line. Our main findings included: a) introduction of indels in exon 22 of SETDB1 sensitized Hs578T to the action of the genotoxic chemotherapy doxorubicin; b) by sequentially introducing indels in exon 22 of SETDB1 and exon 23 of CHD4 and tracking the percentage of the remaining wild-type sequences in the mixed cell populations generated, we obtained evidence of the existence of a synthetic lethality interaction between these genes. Considering the lack of molecular targets in TNBC, our findings provided valuable insights for development of new therapeutic approaches not only for TNBC but also for other cancer types. |
| first_indexed | 2024-03-11T10:43:48Z |
| format | Article |
| id | doaj.art-333e1f700fdb4954b88732a18c01587a |
| institution | Directory Open Access Journal |
| issn | 1414-431X |
| language | English |
| last_indexed | 2024-03-11T10:43:48Z |
| publishDate | 2023-11-01 |
| publisher | Associação Brasileira de Divulgação Científica |
| record_format | Article |
| series | Brazilian Journal of Medical and Biological Research |
| spelling | doaj.art-333e1f700fdb4954b88732a18c01587a2023-11-14T07:52:08ZengAssociação Brasileira de Divulgação CientíficaBrazilian Journal of Medical and Biological Research1414-431X2023-11-015610.1590/1414-431x2023e12854Evidence of a synthetic lethality interaction between SETDB1 histone methyltransferase and CHD4 chromatin remodeling protein in a triple negative breast cancer cell lineM.S. Moraes-Almeidahttps://orcid.org/0000-0003-1502-7700M.C. Sogayarhttps://orcid.org/0000-0003-4805-4609M.A.A. Demasihttps://orcid.org/0000-0003-0488-2015During the tumorigenic process, cancer cells may become overly dependent on the activity of backup cellular pathways for their survival, representing vulnerabilities that could be exploited as therapeutic targets. Certain molecular vulnerabilities manifest as a synthetic lethality relationship, and the identification and characterization of new synthetic lethal interactions may pave the way for the development of new therapeutic approaches for human cancer. Our goal was to investigate a possible synthetic lethal interaction between a member of the Chromodomain Helicase DNA binding proteins family (CHD4) and a member of the histone methyltransferases family (SETDB1) in the molecular context of a cell line (Hs578T) representing the triple negative breast cancer (TNBC), a subtype of breast cancer lacking validated molecular targets for treatment. Therefore, we employed the CRISPR-Cas9 gene editing tool to individually or simultaneously introduce indels in the genomic loci corresponding to the catalytic domains of SETDB1 and CHD4 in the Hs578T cell line. Our main findings included: a) introduction of indels in exon 22 of SETDB1 sensitized Hs578T to the action of the genotoxic chemotherapy doxorubicin; b) by sequentially introducing indels in exon 22 of SETDB1 and exon 23 of CHD4 and tracking the percentage of the remaining wild-type sequences in the mixed cell populations generated, we obtained evidence of the existence of a synthetic lethality interaction between these genes. Considering the lack of molecular targets in TNBC, our findings provided valuable insights for development of new therapeutic approaches not only for TNBC but also for other cancer types.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2023000100688&lng=en&tlng=enBreast cancerSynthetic lethalityCRISPR-Cas9CHD4 chromatin remodeling proteinSETDB1 histone methyltransferase |
| spellingShingle | M.S. Moraes-Almeida M.C. Sogayar M.A.A. Demasi Evidence of a synthetic lethality interaction between SETDB1 histone methyltransferase and CHD4 chromatin remodeling protein in a triple negative breast cancer cell line Brazilian Journal of Medical and Biological Research Breast cancer Synthetic lethality CRISPR-Cas9 CHD4 chromatin remodeling protein SETDB1 histone methyltransferase |
| title | Evidence of a synthetic lethality interaction between SETDB1 histone methyltransferase and CHD4 chromatin remodeling protein in a triple negative breast cancer cell line |
| title_full | Evidence of a synthetic lethality interaction between SETDB1 histone methyltransferase and CHD4 chromatin remodeling protein in a triple negative breast cancer cell line |
| title_fullStr | Evidence of a synthetic lethality interaction between SETDB1 histone methyltransferase and CHD4 chromatin remodeling protein in a triple negative breast cancer cell line |
| title_full_unstemmed | Evidence of a synthetic lethality interaction between SETDB1 histone methyltransferase and CHD4 chromatin remodeling protein in a triple negative breast cancer cell line |
| title_short | Evidence of a synthetic lethality interaction between SETDB1 histone methyltransferase and CHD4 chromatin remodeling protein in a triple negative breast cancer cell line |
| title_sort | evidence of a synthetic lethality interaction between setdb1 histone methyltransferase and chd4 chromatin remodeling protein in a triple negative breast cancer cell line |
| topic | Breast cancer Synthetic lethality CRISPR-Cas9 CHD4 chromatin remodeling protein SETDB1 histone methyltransferase |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2023000100688&lng=en&tlng=en |
| work_keys_str_mv | AT msmoraesalmeida evidenceofasyntheticlethalityinteractionbetweensetdb1histonemethyltransferaseandchd4chromatinremodelingproteininatriplenegativebreastcancercellline AT mcsogayar evidenceofasyntheticlethalityinteractionbetweensetdb1histonemethyltransferaseandchd4chromatinremodelingproteininatriplenegativebreastcancercellline AT maademasi evidenceofasyntheticlethalityinteractionbetweensetdb1histonemethyltransferaseandchd4chromatinremodelingproteininatriplenegativebreastcancercellline |