Chemotherapy-induced executioner caspase activation increases breast cancer malignancy through epigenetic de-repression of CDH12

Abstract

Cancer relapse and metastasis are major obstacles for effective treatment. One important mechanism to eliminate cancer cells is to induce apoptosis. Activation of executioner caspases is the key step in apoptosis and was considered “a point of no return”. However, in recent years, accumulating evidence has demonstrated that cells can survive executioner caspase activation in response to apoptotic stimuli through a process named anastasis. Here we show that breast cancer cells that have survived through anastasis (anastatic cells) after exposure to chemotherapeutic drugs acquire enhanced proliferation and migration. Mechanistically, cadherin 12 (CDH12) is persistently upregulated in anastatic cells and promotes breast cancer malignancy via activation of ERK and CREB. Moreover, we demonstrate that executioner caspase activation induced by chemotherapeutic drugs results in loss of DNA methylation and repressive histone modifications in the CDH12 promoter region, leading to increased CDH12 expression. Our work unveils the mechanism underlying anastasis-induced enhancement in breast cancer malignancy, offering new therapeutic targets for preventing post-chemotherapy cancer relapse and metastasis.

Novel early-onset Alzheimer-associated genes influence risk through dysregulation of glutamate, immune activation, and intracell signaling pathways

“…CDH12 codes for the Cadherin 12 protein which functions in calcium-dependent cell adhesion and is implicated in synaptogenesis, cell junction organization, and ERK signaling 28,29 . According to data from Agora, CDH12 is signi cantly downregulated in seven AD-relevant brain regions (Table S13), so this is consistent with expectations given lower ERK signaling 51 . Regarding K + dysregulation, we also see enrichment in potassium transport pathways implicating TREM2, BIN1, and our novel prioritized gene ALG10B (Table S15).…”

“…Glutamate release into the synaptic space drives CA 2+ transport into NMDA receptors 47,49,50,67,68 , which in turns modulates calmodulin-binding and signaling pathways which are downstream of it 47,49 . These downstream pathways include ERK signaling, which is modulated in part by CDH12 51 and NF-kappa-B signaling, which is modulated in part by LRRC25 69 . Glia cells may also fail to transport glutamate out of the synaptic space because of ALG10B dysfunction and subsequent dysregulation of potassium channels that enable glutamate uptake 48 .…”

When Therapy-Induced Cancer Cell Apoptosis Fuels Tumor Relapse

“…The molecular basis for anastasis-driven tumor angiogenesis and metastasis is emerging. Three recent reports from the laboratory of Gongping Sun, for example, have demonstrated roles for cIAP2/NFκB [46], CDH12 [47], and p38 MAPK signaling [48] in these processes.…”