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The CASP3 Prodomain Regulates Human Cell Survival and Proliferation

ABSTRACT: CASPASE-3 (CASP3) is well known for its proteolytic function that mediates multiple key cell death-initiated processes and other related cellular processes. However, the possibility that CASP3 may also possess important additional non-catalytic functions in mammalian cells has remained largely unexplored. We now report the results of CASP3 knockdown, rescue, proteomic analysis and flow cytometry experiments initially in normal and malignant human mammary cells and later shown to extent to all other human cell types tested. The results reveal a new role of the CASP3 prodomain in regulating the cell cycle progression, survival, proliferation, and protein aggregate accumulation in all cells tested. The generality of these findings suggests that the ancestral pro-survival role of CASP3 in yeast persisted throughout evolution via a conservation of its prodomain, predating its later acquisition of an inherent catalytic property and subsequently preserved cell death control functions.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Cancer Cell

SUBMITTER: Gian Luca Negri

LAB HEAD: Dr Gregg Morin

PROVIDER: PXD045234 | Pride | 2024-01-17

REPOSITORIES: Pride

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Project description:Estrogen receptor positive breast cancer is the most prevalent form of breast cancer. Although a number of available drugs are highly effective at blocking estrogen mediated receptor activity, thousands of patients die every year from ER positive breast cancers because the disease progresses to a stage at which these drugs are no longer effective. Thus, it is crucial to establish a comprehensive understanding of the biology of the estrogen receptor (ER) in ER:positive breast cancers that progress despite hormone therapy, a gap in knowledge that remains a serious impediment to successful treatment of patients with ER positive breast cancer. A key question that must be answered is how the estrogen receptor retains the capacity to activate transcription in the absence or near absence of estrogen. We have found a partial answer to this question upon investigating the effect of amplification and overexpression of Wolf Hirschhorn Syndrome Candidate 1:Like 1 (WHSC1L1), a gene that is amplified in 15% of breast cancers that codes for a histone:lysine methyltransferase. WHSC1L1 lies in the 8p11:p12 amplicon, a region of gene amplification that is strongly associated with breast cancer. In this study, we performed shRNA knockdown of the catalytically inactive short isoform of WHSC1L1 in SUM44PE breast cancer cells and found that expression of the short isoform of WHSC1L1 is necessary for expression of the estrogen receptor in this highly ER:positive cell line. In addition, we found that the estrogen receptor binds chromatin extensively in the absence of exogenous estrogen, including several actively transcribed canonical ER target genes, indicating that estrogen receptor signaling is active in SUM44 cells in estrogen free conditions. These findings represent a novel model for ER biology in luminal B breast cancers harboring amplification of WHSC1L1 and provide insight into the mechanisms by which ER: positive breast cancers become unresponsive to SERMs or aromatase inhibitors.

Dataset Information

The CASP3 Prodomain Regulates Human Cell Survival and Proliferation

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