NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells.
High aldehyde dehydrogenase (ALDH) activity is a marker commonly used to isolate stem cells, particularly breast cancer stem cells (CSCs). Here, we determined that ALDH1A1 activity is inhibited by acetylation of lysine 353 (K353) and that acetyltransferase P300/CBP-associated factor (PCAF) and deacetylase sirtuin 2 (SIRT2) are responsible for regulating the acetylation state of ALDH1A1 K353. Evaluation of breast carcinoma tissues from patients revealed that cells with high ALDH1 activity have low ALDH1A1 acetylation and are capable of self-renewal. Acetylation of ALDH1A1 inhibited both the stem cell population and self-renewal properties in breast cancer. Moreover, NOTCH signaling activated ALDH1A1 through the induction of SIRT2, leading to ALDH1A1 deacetylation and enzymatic activation to promote breast CSCs. In breast cancer xenograft models, replacement of endogenous ALDH1A1 with an acetylation mimetic mutant inhibited tumorigenesis and tumor growth. Together, the results from our study reveal a function and mechanism of ALDH1A1 acetylation in regulating breast CSCs.
Di
D
Zhao
Yan
Y
Mo
Meng-Tian
MT
Li
Shao-Wu
SW
Zou
Zhou-Li
ZL
Cheng
Yi-Ping
YP
Sun
Yue
Y
Xiong
Kun-Liang
KL
Guan
Qun-Ying
QY
Lei
D000107:Acetylation; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D050697:Retinal Dehydrogenase; D015398:Signal Transduction; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D000444:Aldehyde Dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D009363:Neoplasm Proteins; D051880:Receptors, Notch; D050697:Retinal Dehydrogenase; D056565:Sirtuin 2; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C510223:ALDH1A1 protein, human; C474199:SIRT2 protein, human