AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis.
Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with Pten deletion to produce a metastasis-prone tumor. Conversely, genetic ablation of Whsc1 prevented tumor progression in PTEN-null mice. Molecular characterization revealed that increased AKT activity due to PTEN loss directly phosphorylates WHSC1 at S172, preventing WHSC1 degradation by CRL4Cdt2 E3 ligase. Increased WHSC1 expression transcriptionally upregulates expression of RICTOR, a pivotal component of mTOR complex 2 (mTORC2), to further enhance AKT activity. Therefore, the AKT/WHSC1/mTORC2 signaling cascade represents a vicious feedback loop that elicits unrestrained AKT signaling. Furthermore, we determined that WHSC1 positively regulates Rac1 transcription to increase tumor cell motility. The biological importance of a WHSC1-mediated signaling cascade is substantiated by patient sample analysis in which WHSC1 signaling is tightly correlated with disease progression and recurrence. Taken together, our findings highlight a pivotal link between an epigenetic regulator, WHSC1, and key intracellular signaling molecules, AKT, RICTOR, and Rac1, to drive PCa metastasis.
Ni
N
Li
Wei
W
Xue
Huairui
H
Yuan
Baijun
B
Dong
Yufeng
Y
Ding
Yongfeng
Y
Liu
Min
M
Jiang
Shan
S
Kan
Tongyu
T
Sun
Jiale
J
Ren
Qiang
Q
Pan
Xiang
X
Li
Peiyuan
P
Zhang
Guohong
G
Hu
Yan
Y
Wang
Xiaoming
X
Wang
Qintong
Q
Li
Jun
J
Qin
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002465:Cell Movement; D004795:Enzyme Stability / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D011495:Histone-Lysine N-Methyltransferase; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D009479:Neuropeptides; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein; C484602:Rac1 protein, mouse; C525637:rictor protein, mouse; C543213:WHSC1 protein, mouse; C487757:Pten protein, mouse