Trends in Cell Biology

Trends in Cell Biology

Volume 33, Issue 4, April 2023, Pages 280-292
Journal home page for Trends in Cell Biology

Opinion
ΔNp63α in cancer: importance and therapeutic opportunities

https://doi.org/10.1016/j.tcb.2022.08.003Get rights and content

Highlights

  • ΔNp63α is a p63 isoform in the p53 family that is a master regulator of epithelial stemness in normal tissue.

  • In cancer, ΔNp63α regulates a number of key aspects of cancer progression, including cancer stem cell (CSC) maintenance, metastasis, and drug resistance, through regulation of several downstream pathways.

  • ΔNp63α is difficult to target directly, but multiple pathways upstream of ΔNp63α with druggable targets have been identified that represent potential therapeutic opportunities in cancer.

  • Many pathways upstream of ΔNp63α are involved in crosstalk with the tumor microenvironment. With growing interest in targeting the tumor niche, further investigation into how ΔNp63α is involved in crosstalk with the microenvironment represents an exciting area of future investigation.

Our understanding of cancer and the key pathways that drive cancer survival has expanded rapidly over the past several decades. However, there are still important challenges that continue to impair patient survival, including our inability to target cancer stem cells (CSCs), metastasis, and drug resistance. The transcription factor p63 is a p53 family member with multiple isoforms that carry out a wide array of functions. Here, we discuss the critical importance of the ΔNp63α isoform in cancer and potential therapeutic strategies to target ΔNp63α expression to impair the CSC population, as well as to prevent metastasis and drug resistance to improve patient survival.

Section snippets

Cancer stem cells

In adult tissue, stem cells are essential for tissue homeostasis and regeneration. Stem cells are long-lived cells that generate progeny throughout life to regenerate multiple specialized, shorter-lived cells that are essential for various tissue-specific functions [1]. As stem cells are critical to the maintenance of normal tissue, so too are CSCs critical to the maintenance of many tumors. CSCs are broadly defined as cells that possess the ability to initiate tumor growth, self-renew, and

ΔNp63α and stemness

In normal tissue, ΔNp63α is highly expressed in several stem cell compartments, particularly in stratified and glandular epithelial cells [5]. The critical role of ΔNp63α can be seen in p63-deficient mice, which display a lack of all squamous epithelia and their derivatives [2], as well as the severe human developmental defects that occur from germline mutations in p63 (reviewed in [6]). ΔNp63α is required to maintain the self-renewing capacity of epithelial stem cells and is critical for

ΔNp63α in cancer stem cells

ΔNp63α expression has been linked to a CSC phenotype in a number of epithelial cancers, with increased ΔNp63α being associated with elevated numbers of tumor initiating cells, tumorsphere (see Glossary) formation, invasive potential, and enhanced tumorigenicity [7,8]. In squamous cell carcinoma (SCC), the gene encoding stem cell factor SOX2 is coamplified along with the p63 locus and preferentially interacts with the ΔNp63α protein [9]. The gene encoding the chromatin-modifying protein ACTL6A

ΔNp63α in metastasis

Metastasis is the result of a multistep process by which cancer cells travel from the primary tumor through lymphatic or blood vessels to invade distant organs. This complex cascade of events involves a number of signaling pathways that allow for local invasion, survival in circulation, extravasation, and ultimately proliferation at a distant site. CSCs are widely regarded as key drivers of metastasis, as many pathways involved in the CSC phenotype also contribute to the cells’ ability to

Drug resistance

Chemotherapy is one of the principal modes of treatment for cancer, but the effectiveness of chemotherapy is kept in check by drug resistance. Although combination therapies have become the standard for cancer therapy to help circumvent resistance against single-agent treatment, drug resistance continues to be a major obstacle [45], and recent work has linked ΔNp63α to drug resistance in several cell lines. ΔNp63α has been implicated in cisplatin resistance through several mechanisms. In HNSCC,

Druggable targets upstream of ΔNp63α

Because of the difficulties in targeting ΔNp63α directly, we believe targeting upstream regulators of ΔNp63α is a potential therapeutic strategy. Later we discuss what we believe are exciting therapeutic targets upstream of ΔNp63α that could provide a means to reduce ΔNp63α expression and the CSC phenotype, metastasis, and drug resistance associated with it. In Box 1 we discuss several additional compounds that can potentially be used to target ΔNp63α. It is important to note that upstream

BRD4/EZH2

A number of chromatin-modifying proteins have been linked to ΔNp63α (summarized in Figure 2). In pancreatic cancer, loss of KDM6A results in squamous-like metastatic cancers, which are selectively sensitive to bromodomain and extraterminal domain (BET) inhibitors including JQ1 [52]. Treatment with JQ1, which predominantly inhibits bromodomain containing protein (BRD4), reverses squamous differentiation. It was shown that BRD4 binds to ΔNp63α-regulating superenhancers, and treatment with JQ1 not

Signals from the microenvironment

The tumor microenvironment (TME) consists of diverse cell types and ECM components that surround and support the tumor. There is growing interest in targeting the TME due to its critical role in regulating several aspects of cancer progression. Interleukins (ILs) are a key component of the microenvironment, and several have been implicated in regulating ΔNp63α, including IL-1β in MCF7 cells; IL-6 in lung cancer; and IL-13, IL-17, and IL-22 in keratinocytes [48,61., 62., 63., 64.]. ΔNp63α also

Cell surface markers

In addition to the signals released from the TME, cancer cell surface markers are critical in crosstalk with the TME, as they relay those signals to the cancer cells. In line with the importance of signals emanating from the TME in regulating ΔNp63α, many cell surface markers involved in ‘outside in’ signaling have been linked to ΔNp63α as well.

Epidermal growth factor receptor

The tyrosine kinase receptor epidermal growth factor receptor (EGFR) is frequently overexpressed in SCCs, where it has been shown to induce ΔNp63α expression through activation of phosphatidylinositol 3-kinase (PI3K), in turn activating mammalian target of rapamycin (mTOR)-dependent activation of STAT3 [70]. ΔNp63α is also capable of regulating EGFR expression in cooperation with SOX2 and CCAT1 [71], suggesting a possible feedback loop between EGFR and ΔNp63α in SCC. In basal-like

Integrins/TG2/NRP1

Signaling through α6β4 integrin has also been shown to regulate ΔNp63α expression. In SCC, the enzyme transglutaminase 2 (TG2) interacts with α6β4 integrin. This interaction leads to activation of FAK-SRC and PI3K-PDK1 kinases. Signaling through this cascade results in the inhibition of large tumor suppressor kinase 1 (LATS1), an integral component of the Hippo signaling pathway that suppresses YAP [11]. Signaling through this cascade results in the inhibition of LATS1, an integral component of

Wnt/β-catenin pathway

Wnt/β-catenin signaling is a key regulator of stemness through the regulation of self-renewal, pluripotency, differentiation, and migration. In cancer, abnormal activation of Wnt/β-catenin promotes a CSC phenotype and metastasis. [76]. ΔNp63α is under direct control of the WNT/β-catenin pathway through binding of lymphoid enhancer binding factor 1 (Lef1) and β-catenin between the promoters of TAp63 and ΔNp63 [77]. Another layer of regulation comes from a β-catenin responsive element within the

STAT3

Of the seven members of the STAT protein family, STAT3 is arguably the most important for cancer progression [79]. STAT3 is not only critical for transducing signals from multiple receptor and non–receptor tyrosine kinases that are frequently activated in cancer cells; it is also a transcription factor regulating the expression of a wide range of targets that contribute to tumor progression, most notably ΔNp63α [79]. STAT3 binds to the promoter of ΔNp63α in several cell types, and the

Concluding remarks

The transcription factor ΔNp63α is a key regulator of epidermal morphogenesis and epithelial tissue homeostasis. Here, we have discussed evidence supporting the notion that ΔNp63α regulates various aspects of cancer stemness, metastasis, and drug resistance across a number of cancer types. ΔNp63α regulation of these critical features of cancer biology has been linked to the regulation of several pathways, including HELLS, CD44, integrins, WNTs, ILs, and EMT markers. Therefore, impairing ΔNp63α

Acknowledgments

This work was supported by the Office of the Director, National Institutes of Health, through awards 5P30CA045508 (Cancer Center Support Grant), CA225134 (to M.L.F.), CA247400 (to S.B.), as well as R01CA190997 and R21OD018332 (to A.A.M.). This project was also supported through the Cold Spring Harbor Laboratory and Northwell Health Affiliation.

Declaration of interests

The authors declare no conflicts of interest.

Glossary

Anoikis
apoptosis that results from loss of attachment to the extracellular matrix or neighboring cells.
Bortezomib
a dipeptide boronic acid derivative and proteasome inhibitor used to treat multiple myeloma and mantle cell lymphoma.
Cisplatin
an anticancer, antineoplastic, or cytotoxic chemotherapy drug classified as an alkylating agent that works by interfering with DNA replication.
Clonogenic survival
an in vitro cell survival assay based on the ability of a single cell to grow into a colony,

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