Pyroptosis: A new frontier in cancer.

In recent decades, chemotherapies targeting apoptosis have emerged and demonstrated remarkable achievements. However, emerging evidence has shown that chemoresistance is mediated by impairing or bypassing apoptotic cell death. Several novel types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, have recently been reported to play significant roles in the modulation of cancer progression and are considered a promising strategy for cancer treatment. Thus, the switch between apoptosis and pyroptosis is also discussed. Cancer immunotherapy has gained increasing attention due to breakthroughs in immune checkpoint inhibitors; moreover, ferroptosis, necroptosis, and pyroptosis are highly correlated with the modulation of immunity in the tumor microenvironment. Compared with necroptosis and ferroptosis, pyroptosis is the primary mechanism for host defense and is crucial for bridging innate and adaptive immunity. Furthermore, recent evidence has demonstrated that pyroptosis exerts benefits on cancer immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR-T). Hence, in this review, we elucidate the role of pyroptosis in cancer progression and the modulation of immunity. We also summarize the potential small molecules and nanomaterials that target pyroptotic cell death mechanisms and their therapeutic effects on cancer.

Inflammation-related pyroptosis, a novel programmed cell death pathway, and its crosstalk with immune therapy in cancer treatment.

The YAP1/Hippo and p53 pathways are critical protectors of genome integrity in response to DNA damage. Together, these pathways secure cellular adaptation and maintain overall tissue integrity through transcriptional re-programing downstream of various environmental and biological cues generated during normal tissue growth, cell proliferation, and apoptosis. Genetic perturbations in YAP1/Hippo and p53 pathways are known to contribute to the cells' ability to turn rogue and initiate tumorigenesis. The Hippo and p53 pathways cooperate on many levels and are closely coordinated through multiple molecular components of their signaling pathways. Several functional and physical interactions have been reported to occur between YAP1/Hippo pathway components and the three p53 family members, p53, p63, and p73. Primarily, functional status of p53 family proteins dictates the subcellular localization, protein stability and transcriptional activity of the core component of the Hippo pathway, Yes-associated protein 1 (YAP1). In this review, we dissect the critical points of crosstalk between the YAP1/Hippo pathway components, with a focus on YAP1, and the p53 tumor suppressor protein family. For each p53 family member, we discuss the biological implications of their interaction with Hippo pathway components in determining cell fate under the conditions of tissue homeostasis and cancer pathogenesis.

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Reciprocal Crosstalk Between YAP1/Hippo Pathway and the p53 Family Proteins: Mechanisms and Outcomes in Cancer

Despite the decline in death rate from breast cancer and recent advances in targeted therapies and combinations for the treatment of metastatic disease, metastatic breast cancer remains the second leading cause of cancer-associated death in US women The invasion–metastasis cascade involves a number of steps and multitudes of proteins and signaling molecules The pathways include invasion, intravasation, circulation, extravasation, infiltration into a distant site to form a metastatic niche, and micrometastasis formation in a new environment Each of these processes is regulated by changes in gene expression Noncoding RNAs including microRNAs (miRNAs) are involved in breast cancer tumorigenesis, progression, and metastasis by post-transcriptional regulation of target gene expression miRNAs can stimulate oncogenesis (oncomiRs), inhibit tumor growth (tumor suppressors or miRsupps), and regulate gene targets in metastasis (metastamiRs) The goal of this review is to summarize some of the key miRNAs that regulate genes and pathways involved in metastatic breast cancer with an emphasis on estrogen receptor α (ERα+) breast cancer We reviewed the identity, regulation, human breast tumor expression, and reported prognostic significance of miRNAs that have been documented to directly target key genes in pathways, including epithelial-to-mesenchymal transition (EMT) contributing to the metastatic cascade We critically evaluated the evidence for metastamiRs and their targets and miRNA regulation of metastasis suppressor genes in breast cancer progression and metastasis It is clear that our understanding of miRNA regulation of targets in metastasis is incomplete

Regulation of breast cancer metastasis signaling by miRNAs

The biological functions of long non‑coding RNAs (lncRNAs) in cancer have not been fully elucidated. The present study demonstrated that the expression of a newly identified lncRNA, RP1‑85F18.6, was upregulated in colorectal cancer (CRC) tissues and cell lines. Knockdown of lncRNA RP1‑85F18.6 served a key role in tumor inhibition, reduced cell proliferation and invasion, disrupted the cell cycle, and increased apoptosis and pyroptosis of CRC cells. Conversely, overexpression of lncRNA RP1‑85F18.6 exerted the opposite effects. Furthermore, silencing lncRNA RP1‑85F18.6 decreased ΔNp63 expression at both the mRNA and protein levels. Furthermore, co‑transfection with ΔNp63 siRNA and lncRNA RP1‑85F18.6‑expressing vector attenuated the tumor‑promoting effects of lncRNA RP1‑85F18.6 overexpression. The expression levels of lncRNA RP1‑85F18.6, ΔNp63 and gasdermin D (GSDMD) were revealed to be associated with lymph node and distant metastases in patients with CRC, and therefore may serve as predictors in CRC. The findings of the present study suggested that lncRNA RP1‑85F18.6 may trigger CRC cell proliferation, invasion and cell cycle disruption, and suppress apoptosis and pyroptosis of CRC cells through regulating ΔNp63 expression. Therefore, lncRNA RP1‑85F18.6 and ΔNp63 may be considered unfavorable biomarkers, whereas GSDMD may be a favorable biomarker in CRC; these markers may prove valuable in the future diagnosis and prognosis of CRC.

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Biological functions and clinical significance of the newly identified long non‑coding RNA RP1‑85F18.6 in colorectal cancer

As a member of tumor suppressor p53 family, p63, a gene encoding versatile protein variant, has been documented to correlate with cancer formation and progression, though it is rarely mutated in cancer patients. However, it has long been controversial on whether p63 is an oncogene or a tumor suppressor. Here, we comprehensively reviewed reports on roles of p63 in development, tumorigenesis and tumor progression. According to data from molecular cell biology, genetic models and clinic research, we conclude that p63 may act as either an oncogene or a tumor suppressor gene in different scenarios: TA isoforms of p63 gene are generally tumor-suppressive through repressing cell proliferation, survival and metastasis; ΔN isoforms, however, may initiate tumorigenesis via promoting cell proliferation and survival, but inhibit tumor metastasis and progression; effects of p63 on tumor formation and progression depend on the context of the whole p53 family, and either amplification or loss of p63 gene locus can break the balance to cause tumorigenesis.

A double dealing tale of p63: an oncogene or a tumor suppressor.

p63 and c-Myc are key transcription factors controlling genes involved in the cell cycle and cellular senescence. We previously reported that p63α can destabilize MM1 protein to derepress c-Myc, resulting in cell cycle progress and tumorigenesis. However, how the proteasomal degradation of MM1 is facilitated remains unclear. In the present study, we identified a novel E3 ligase, HERC3, which can mediate ubiquitination of MM1 and promote its proteasome-dependent degradation. We found that ΔNp63α transcriptionally up-regulates HERC3 and knockdown of HERC3 abrogates ΔNp63α-induced down-regulation of MM1. Either overexpression of MM1 or ablation of HERC3 induces cell senescence, while knockdown of MM1 rescues cell senescence induced by deficiency of either ΔNp63α or HERC3, implicating the involvement of the ΔNp63α/HERC3/MM1/c-Myc axis in the modulation of cell senescence. Additionally, our Oncomine analysis indicates activation of the ΔNp63α/HERC3/MM1/c-Myc axis in invasive breast carcinoma. Together, our data illuminate a novel axis regulating cell senescence: ΔNp63α stimulates transcription of E3 ligase HERC3, which mediates ubiquitination of c-Myc modulator MM1 and targets it to proteasomal degradation; subsequently, c-Myc is derepressed by ΔNp63α, thereby cell senescence is modulated by this axis. Our work provides a new interpretation of crosstalk between p63 and c-Myc, and also sheds new light on ΔNp63α-controlled cell senescence and tumorigenesis.

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ΔNp63α down-regulates c-Myc modulator MM1 via E3 ligase HERC3 in the regulation of cell senescence

ΔNp63αplays key roles in cell survival and proliferation. So its expression is always tightly controlled in cells. We previously reported that DNA damage down-regulates transcription of ΔNp63αin FaDu and HaCat cells, which contributes to cell apoptosis. In the present study, we found that DNA damage induces down-regulation of ΔNp63αvia facilitating its proteasomal degradation in cell lines such as MDA-MB-231 and MCF10A. Further investigation revealed that transcription of WWP1 is stimulated by DNA damage in these cells. Knock-down of WWP1 abrogates DNA damage-induced down-regulation of ΔNp63αand partially rescues cell apoptosis. Interestingly, DNA damage may stimulate WWP1 through different mechanisms in different cell types: it up-regulates transcription of WWP1 in a p53-dependent manner in MCF10A and HEK293 cells, while miR-452 may be involved in DNA damage-induced up-regulation of WWP1 in MDA-MB-231 cells. Our study demonstrates a novel pathway which regulates ΔNp63αupon cellular response to chemotherapeutic agents.

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DNA damage induces expression of WWP1 to target ΔNp63α to degradation.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1002/1873-3468.13104

Cullin3/KCTD5 induces monoubiquitination of ΔNp63α and impairs its activity.

Background ΔNp63α and c-Myc are key transcription factors controlling proliferation and senescence in epithelial cells. We previously reported that the c-Myc modulator MM1 and its E3 ligase, HERC3, together with the transcription factor ΔNp63α, compose a feedback loop, which regulates proliferative senescence in MCF-10A mammary epithelial cells. However, it is unknown whether this loop is involved in skin ageing. On the other hand, ultraviolet B (UVB) rays are assumed to be the main culprits for photoageing of the epidermis, but the underlying mechanisms are obscure. Aims To investigate whether MM1/ΔNp63α axis is involved in UVB-induced photoageing of the epidermis. Materials and methods HaCaT human immortalized keratinocytes overexpressed with MM1, knocked down with c-Myc or irradiated with UVB, were subjected to MTT assays to measure cell proliferation, as well as RT-qPCR or immunoblot to detect the members of MM1/ΔNp63α loop and the cellular senescence markers. Meanwhile, primary normal human keratinocytes (NHKs) or mice were irradiated with UVB, followed by immunoblot analysis, SA-β-gal, haematoxylin-eosin or immunohistochemistry staining. Results Overexpression of MM1 down-regulated ΔNp63α and induced proliferative senescence in the HaCaT cells. In the HaCaT cells, NHKs and the mouse epidermis, UVB irradiation increased MM1 mRNA level and led to a down-regulation of ΔNp63α, HERC3 and c-Myc, concomitant with cellular senescence or photoageing. Additionally, knock-down of c-Myc induced proliferative senescence in the HaCaT cells and abrogated UVB-induced cellular senescence. Conclusions UVB up-regulates MM1 and consequently modulates ΔNp63α and c-Myc, which may account for the proliferative senescence of keratinocytes and photoageing of the epidermis.

Shijie Fan

Papers

A double dealing tale of p63: an oncogene or a tumor suppressor.

ΔNp63α down-regulates c-Myc modulator MM1 via E3 ligase HERC3 in the regulation of cell senescence

DNA damage induces expression of WWP1 to target ΔNp63α to degradation.

Cullin3/KCTD5 induces monoubiquitination of ΔNp63α and impairs its activity.

Ultraviolet B irradiation up-regulates MM1 and induces photoageing of the epidermis