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Shared and independent functions of aPKC? and Par3 in skin tumorigenesis.

ABSTRACT: The polarity proteins Par3 and aPKC are key regulators of processes altered in cancer. Par3/aPKC are thought to dynamically interact with Par6 but increasing evidence suggests that aPKC and Par3 also exert complex-independent functions. Whereas aPKC? serves as tumor promotor, Par3 can either promote or suppress tumorigenesis. Here we asked whether and how Par3 and aPKC? genetically interact to control two-stage skin carcinogenesis. Epidermal loss of Par3, aPKC?, or both, strongly reduced tumor multiplicity and increased latency but inhibited invasion to similar extents, indicating that Par3 and aPKC? function as a complex to promote tumorigenesis. Molecularly, Par3/aPKC? cooperate to promote Akt, ERK and NF-?B signaling during tumor initiation to sustain growth, whereas aPKC? dominates in promoting survival. In the inflammatory tumorigenesis phase Par3/aPKC? cooperate to drive Stat3 activation and hyperproliferation. Unexpectedly, the reduced inflammatory signaling did not alter carcinogen-induced immune cell numbers but reduced IL-4 Receptor-positive stromal macrophage numbers in all mutant mice, suggesting that epidermal aPKC? and Par3 promote a tumor-permissive environment. Importantly, aPKC? also serves a distinct, carcinogen-independent role in controlling skin immune cell homeostasis. Collectively, our data demonstrates that Par3 and aPKC? cooperate to promote skin tumor initiation and progression, likely through sustaining growth, survival, and inflammatory signaling.

SUBMITTER: Vorhagen S

PROVIDER: S-EPMC6137026 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis.

Vorhagen Susanne S Kleefisch Dominik D Persa Oana-Diana OD Graband Annika A Schwickert Alexandra A Saynisch Michael M Leitges Michael M Niessen Carien M CM Iden Sandra S

Oncogene 20180523 37

The polarity proteins Par3 and aPKC are key regulators of processes altered in cancer. Par3/aPKC are thought to dynamically interact with Par6 but increasing evidence suggests that aPKC and Par3 also exert complex-independent functions. Whereas aPKCλ serves as tumor promotor, Par3 can either promote or suppress tumorigenesis. Here we asked whether and how Par3 and aPKCλ genetically interact to control two-stage skin carcinogenesis. Epidermal loss of Par3, aPKCλ, or both, strongly reduced tumor m ...[more]

PMID: 29789715

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Project description:Prostate cancer (PCa) is one of the most frequent tumors and leading cause of cancer deaths among males worldwide. The majority of deaths are due to recurrence and subsequent development of the metastatic cancer. Although loss or dislocalization of polarity proteins has been implicated in embryogenesis deficiency and tumorigenesis, association of polarity protein expression levels with tumor metastasis remains unclear.Bioinformatics, qRT-PCR, western blot and immunohistochemical (IHC) analyses were used to examine expression of Par3, a key component of polarity-associated partitioning defective (PAR) complex, in primary and metastatic clinical PCa samples. Loss-of-function and gain-of-function studies in vitro and in vivo were performed to determine the functions of Par3 during metastasis of PCa. Co-immunoprecipitation (co-IP), western blot, immunofluorescence (IF), chromatin immunoprecipitation (ChIP) and qRT-PCR analyses were conducted to investigate the underlying mechanism for the function of Par3 on PCa metastasis.In this study, we found that elevated expression of Par3 is positively associated with PCa metastasis. Knockdown of Par3 inhibits PCa cell migration and invasion in vitro and tumor metastasis in vivo, whereas overexpression of Par3 yields the opposite results. Mechanistically, Par3 suppresses phosphorylation of LATS to inactivate the Hippo pathway and enhances nuclear translocation of YAP by sequestrating KIBRA from the KIBRA/Merlin/FRMD6 complex and forming a Par3/aPKC/KIBRA complex. Stable knockdown of Par3 leads to restoration of the KIBRA/Merlin/FRMD6 complex and activation of the Hippo pathway, and then results in an inhibition on YAP nuclear translocation. In addition, in conjunction with the TEA domain (TEAD) transcription factor family, intranuclear YAP promotes the transcription of several pro-metastatic genes such as the matrix metalloproteinase (MMP) family, Zeb1, Snail1 and Twist1. Moreover, knockdown of Par3 downregulates expression of these pro-metastatic genes.Our findings indicate that elevated expression of Par3 promotes PCa metastasis via KIBRA sequestration-mediated inactivation of the Hippo pathway to upregulate expression of pro-metastatic genes. Downregulation of Par3 expression may serve as a potential treatment approach for PCa metastasis by activating the Hippo pathway.

Dataset Information

Shared and independent functions of aPKC? and Par3 in skin tumorigenesis.

Publications

Shared and independent functions of aPKCλ and Par3 in skin tumorigenesis.

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