A Metabolic-Epigenetic Mechanism Directs Cell Fate and Therapeutic Sensitivity in Breast Cancer.

Over the past decade, studies have increasingly shed light on a reciprocal relationship between cellular metabolism and cell fate, meaning that a cell's lineage both drives and is governed by its specific metabolic features. A recent study by Zhang and colleagues, published in Cell Metabolism, describes a novel metabolic-epigenetic regulatory axis that governs lineage identity in triple-negative breast cancer (TNBC). Among the key findings, the authors demonstrate that the metabolic enzyme pyruvate kinase M2 (PKM2) directly binds to the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in the nucleus to silence expression of a set of genes that includes the mitochondrial carnitine transporter SLC16A9. Perturbation of this metabolic-epigenetic regulatory mechanism induces a metabolic shift away from glycolysis and toward fatty acid oxidation. The ensuing influx of carnitine facilitates the deposition of the activating epigenetic mark H3K27Ac onto the promoter of GATA3, driving a committed luminal lineage state. Importantly, this metabolic-epigenetic axis represents a potentially targetable vulnerability for the treatment of TNBC, a subtype that currently lacks effective therapeutic strategies. These findings lend further support for the paradigm shift underlying our understanding of cancer metabolism: that a cellular fuel source functions not only to provide energy but also to direct the epigenetic regulation of cell fate.

MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer.

Advanced prostate cancers are treated with therapies targeting the androgen receptor (AR) signaling pathway. While many tumors initially respond to AR inhibition, nearly all develop resistance. It is critical to understand how prostate tumor cells respond to AR inhibition in order to exploit therapy-induced phenotypes prior to the outgrowth of treatment-resistant disease. Here, we comprehensively characterize the effects of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. The metabolic response to AR inhibition is defined by reduced glycolysis, robust elongation of mitochondria, and increased reliance on mitochondrial oxidative metabolism. We establish DRP1 activity and MYC signaling as mediators of AR-blockade-induced metabolic phenotypes. Rescuing DRP1 phosphorylation after AR inhibition restores mitochondrial fission, while rescuing MYC restores glycolytic activity and prevents sensitivity to complex I inhibition. Our study provides insight into the regulation of treatment-induced metabolic phenotypes and vulnerabilities in prostate cancer.

Prostatic proliferative inflammatory atrophy: welcome to the club†.

Single-cell RNA sequencing studies in the human prostate have defined a population of epithelial cells with transcriptional similarities to club cells in the lung. However, the localization of club-like cells in the human prostate, and their relationship to prostate cancer, is poorly understood. In a new article in The Journal of Pathology, RNA in situ hybridization was used to demonstrate that club cell markers are expressed in luminal cells adjacent to inflammation in the peripheral zone of the human prostate, where prostate cancer tends to arise. These club-like cells are commonly found in proliferative inflammatory atrophy (PIA) lesions and express markers consistent with an intermediate epithelial cell-type. Future studies will be needed to understand the functional role of club-like cells in human prostate inflammation, regeneration, and disease. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

TAOK2 is an ER-localized kinase that catalyzes the dynamic tethering of ER to microtubules.

The endoplasmic reticulum (ER) depends on extensive association with the microtubule (MT) cytoskeleton for its structure and mitotic inheritance. However, mechanisms that underlie coupling of ER membranes to MTs are poorly understood. We have identified thousand and one amino acid kinase 2 (TAOK2) as a pleiotropic protein kinase that mediates tethering of ER to MTs. In human cells, TAOK2 localizes in distinct ER subdomains via transmembrane helices and an adjacent amphipathic region. Through its C-terminal tail, TAOK2 directly binds MTs, coupling ER membranes to the MT cytoskeleton. In TAOK2 knockout cells, although ER-membrane dynamics are increased, movement of ER along growing MT plus ends is disrupted. ER-MT tethering is tightly regulated by catalytic activity of TAOK2, perturbation of which leads to defects in ER morphology, association with MTs, and cell division. Our study identifies TAOK2 as an ER-MT tether and reveals a kinase-regulated mechanism for control of ER dynamics.

East Asian child-rearing attitudes: an exploration of cultural, demographic and self-disclosure factors among US immigrants.

Child-rearing attitudes among East Asian groups have been emphasized in the developmental psychology literature in the context of their association with academic achievement. Although child-rearing attitudes play an important role in the transmission of cultural values, much of the research on East Asian child-rearing attitudes has ignored cultural variables and has instead focused on authoritarian parenting style. The current study examined the association between three classes of variables-culture (i.e., ethnic identity, self-construal, acculturation), demographics (sex, years in the US, English fluency), and self-disclosure-and traditional child-rearing attitudes (TCRA) among East Asian immigrants in the United States. It was hypothesized that higher levels of TCRA would be associated with higher levels of ethnic identity, interdependent self-construal, separation, and guarded self-disclosure, and fewer years spent in the United States. The participants included 170 East Asian (Chinese, Japanese, and Korean) immigrants (88 men, 82 women) who were administered a battery of psychometrically established measures. Our hypotheses were largely supported. We found that, while there was no significant sex by ethnicity effect for TCRA, men were significantly more likely than women to endorse TCRA and the Korean group had significantly higher TCRA than the Japanese group. Ethnic identity, interdependent self-construal, separation, years in the US, and guarded self-disclosure were significant independent predictors of TCRA. The findings suggest the need for broadening the content of assessment tools of child-rearing attitudes and measuring associated cultural and noncultural variables among East Asian ethnic groups. Future research on child-rearing attitudes among Asian ethnic groups may benefit from (1) measuring multiple dimensions of TCRA, (2) assessing associated cultural variables directly rather than inferring them in an ad hoc fashion based on observed ethnicity differences, (3) measurement of demography (including sex and years spent in the host country) and (4) examining the potential influence of guarded self-disclosure.

Counselors' Experiences Treating Methadone-maintained Patients with Chronic Pain: A Needs Assessment Study.

PURPOSE: : This study was designed to conduct a needs assessment concerning methadone counselors' experiences working with methadone-maintained patients with chronic pain and measure counselors' interest in receiving specialized training to treat such patients. METHODS: : A survey, developed by the authors, was administered to 25 counselors with a combined caseload of 956 patients at 3 opioid agonist treatment programs. RESULTS: : Patients with chronic pain comprised 27% of counselors' overall caseloads. Counselors believed that, on average, 46% of these patients' pain had a psychologic component and 56% exhibited continued drug use, which patients attributed to ongoing pain. Twenty-three counselors reported an interest in receiving specialized training in treating chronic pain. A variety of management issues, including monitoring the use of pain medications and providing pain management referrals, were reported. CONCLUSIONS: : Findings from this needs assessment study suggest specific targets, which may be important to consider, in prospective specialized methadone maintenance treatment (MMT) counselor training and counseling for MMT patients with chronic pain.

Gender, sex role ideology, and self-esteem among East Asian immigrants in the United States.

This study examined the relationship between gender, sex role ideology, and self-esteem among 170 (88 male, 82 female) East Asian immigrants in the United States. Participants were administered a battery of psychometrically established measures. Men and women did not differ on personal or collective self-esteem (CSE). Women who endorsed traditional sex roles were significantly more likely to report higher private, identity, and total CSE. Personal self-esteem was a significant independent predictor of traditional sex role for women. Participants who endorsed sex role equality were significantly more likely to report public, membership, and total CSE. Sex role equality was associated with enhanced private CSE for men and attenuated personal self-esteem for women. These findings point to the importance of assessing multiple facets of self-esteem, which appear to be differentially associated with sex role ideology for men and women.