Acetylation Inhibits LDH-A And ALDH1A1 To Regulate Tumorigenesis And Tumor Growth

Protein lysine acetylation, as a key posttranslational modification, is firstly reported in histones and nuclear transcription regulators. Recently, it has been reported a large number of non-nuclear proteins, especially enzymes involved in intermediate metabolism, are acetylated. Acetylation could regulate their enzymatic activity, protein stability, sub-cellular localization or cross-talk with other modifications.My study includes two parts:one is lysine-5 acetylation negatively regulates lactate dehydrogenases A (LDH-A) and is decreased in pancreatic cancer; another one is Notch stimulates aldehyde dehydrogenase 1A1 (ALDH1A1) deacetylation and activation to promote breast cancer stem cell.PartⅠReprogramming of energy metabolism, particularly the elevated glucose uptake and lactate production, is a hallmark of cancer. Instead of entering mitochondria to fuel the tricarbolic acid (TCA) cycle and oxidative phosphorylation for efficient energy production, a large fraction of pyruvate in cancer cells is converted into lactate by LDH. Moreover, the excess lactate could promote cancer cell migration and invasion. It has long been known that many tumor cells express high levels of LDH-A, including non-small-cell lung cancer, colorectal cancer, and breast cancers. Elevated transcription by c-Myc or HIF1a may contribute to increased LDH-A in some cancer types.My study demonstrates another mechanism of LDH-A up-regulation by post-translational modification in pancreatic cancers. We found that LDH-A is acetylated at lysine 5 (K5) and this acetylation reduces LDH-A catalytic activity. Furthermore, the K5-acetylated LDH-A is recognized by the HSC70 chaperone and delivered to lysosomes for degradation.Replacement of endogenous LDH-A with an acetylation mimetic mutant decreases cancer cell proliferation and migration. Importantly, K5 acetylation of LDH-A is reduced and accompanied with increased LDH-A protein levels in both early and late stages of pancreatic cancers. Taken together, our study not only demonstrates a novel mechanism of LDH-A regulation, but also provides a potential early diagnosis maker and therapeutic target for pancreatic cancer.Part ⅡCancer stem cells (CSCs) possess the ability of tumorigenic potential to give rise to new tumors. CSCs contribute to tumor metastasis, poor prognosis and relapse. Self-renewal, the most important property of CSCs, regulates tumor growth and metastasis. Breast cancer stem cell is the first CSCs isolated and identified from solid malignancy tumors. Therefore, these CSCs are the most intensely studied. Breast CSCs have been enriched in CD44+CD24-/low, CD133+or high ALDH1 activity subpopulations. It has been reported that high ALDH1 activity is not only as breast CSCs marker, but also related to poor prognosis and increased metastasis.My study reports that ALDH1A1 is acetylated at Lysine 353, and this acetylation inhibits its enzymatic activity. We also found the acetyltransferease PCAF and deacetylase SIRT2 are responsible for ALDH1A1 K353 regulation. More importantly, CSCs, the high ALDH1 activity population separated from breast cancer tissues, shows lower K353 acetylation level of ALDH1A1. Replacement of endogenous ALDH1A1 with an acetylation mimetic mutant inhibits self-renewal property of breast CSCs.Moreover, Notch signaling pathway, regulating cell-fate determination and cell proliferation during development, induces SIRT2 expression, thereby leading to ALDH1A1 deacetylation and enzymatic activation to promote self-renewal of breast CSCs. In breast cancer xenografted mouse models, replacement of endogenous ALDH1A1 with an acetylation mimetic mutant inhibits tumorigenesis and tumor growth. Our study reveals a mechanism of ALDH1A1 acetylation regulating breast CSCs, and provides a potential drug target to breast CSCs.